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Garlic

Botanical Name: Allium sativum L.
Pharmacopoeial Name: Alii sativi bulbus.
Synonym: Porvium sativum Rehb.
Common Names: Garlic, stinking rose.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Acetaminophen /	Potential pharmacokinetic interaction caused by garlic inhibition of cytochrome P450 2E1 may reduce hepatoxic metabolite NAPQI formation. Not clinically demonstrated.	Not applicable for management of acute acetaminophen toxicity.
Dipyridamole Antiplatelet thromboprophylactics / /	Possible additive increased antiplatelet activity with dipyridamole. Not established with other antiplatelet agents. Clinical significance not established; increased risk of bleeds likely overstated.	Avoid or adopt and monitor bleed times. Combine garlic in antithrombotic protocols.
Doxorubicin Anthracycline chemotherapy /	Garlic protects against and reduces drug-induced cardiotoxicity through multiple mechanisms, including increasing myocardial antioxidant status. Not clinically demonstrated.	Pretreat, coadminister, and continue herb postchemotherapy in cardioprotective protocols.
HMG-CoA reductase inhibitors (statins) /	Additive inhibition of HMG-CoA theoretically allows lowered statin dose and reduction of drug adverse effects. Plausible but not clinically established.	Consider adopting if statin-induced ADRs (myalgias, fatigue, etc.); trial if symptomatic.
Methotrexate Fluorouracil (5-FU) Chemotherapy associated with mucositis /	Garlic may prevent and reduce chemotherapy-induced mucositis through anti-inflammatory and antioxidant mechanisms. Not clinically established.	Consider incorporating garlic with other agents in protective protocols for chemotherapy-induced mucositis.
Saquinavir Protease inhibitor antiretrovirals /	Possible pharmacokinetic interaction with saquinavir; reduces drug bioavailability; does not occur with ritonavir. Unknown significance and applicability to related protease inhibitors.	Monitoring serum drug levels advisable if coadministered.
Warfarin Oral vitamin K antagonist anticoagulants /	Theoretical additive effects on hemostasis caused by possible platelet inhibition. Clinical studies suggest interaction insignificant.	If coadministered, monitor INR and check for peripheral bleed symptoms.
HMG-CoA , Hydroxymethylglutaryl coenzyme A; ADRs , adverse drug reactions; INR , international normalized ratio.

herb description

Family

Liliaceae.

Related Species

Allium cepa L. (onion), Allium schoenoprasum L. (chives).

Habitat and Cultivation

Originally native to central Asia; commercially cultivated for 5000 years as a food and medicinal herb worldwide.

Parts Used

Fresh or dried bulb.

Common Forms

Fresh bulb.
Dried bulb.
Dried powder (allicin-stabilized).
Aged garlic extract (AGE).
Garlic oil (steam-distilled).
Garlic oil (macerated).

herb in clinical practice

Overview

Garlic dietary supplements consistently occupy second or third place of the top-selling botanical products in the United States, quite apart from the widespread availability and use of garlic cloves as a dietary/culinary herbal ingredient. Scientific studies and numerous clinical trials support the following three primary areas of use in modern practice:

For cardiovascular disease prevention and treatment as a hypolipidemic, antiatherosclerotic, hypotensive, antiplatelet, and fibrinolytic agent.
For infectious conditions as a broad-spectrum antibiotic, antifungal, antiviral, and anthelmintic agent.
As a chemopreventive and anticancer agent; antioxidant and immunostimulant properties impact each of these areas.
The pharmacology of the herb derives from its organosulfur constituents (OSCs), although the chemistry of these is extremely complex and has not been fully characterized. Importantly, different garlic preparations may have significantly different constituent profiles; the principal compounds in the intact bulb are gamma-glutamyl cysteine peptides and the cysteine sulfoxide alliin. The enzyme allinase (released by damage to intact cells) converts alliin to the thiosulfinate allicin. Allicin is unstable and degrades to various volatile sulfide congeners, depending on the conditions applied. Steam distillation converts water-soluble thiosulfinates to oil-soluble diallyl sulfides, whereas oil maceration produces ajoenes and vinyldithins.
Similarly, pharmacokinetic differences exist among the various preparations and their components. Metabolic transformation of various sulfides leads to the formation of compounds that have modulating effects on the cytochrome P450 (CYP450) system. Enteric-coated preparations have been shown to release only a fraction of their active allicin content.
These differences complicate attempts to compare data from various experimental and clinical trials using different garlic preparations. More than 45 randomized clinical trials have been conducted with garlic preparations. Metastudies have concluded that these trials show positive, although limited, short-term benefits of garlic on serum cholesterol and some coagulation parameters, but no significant effect on hypertension or blood glucose levels. ^1-4Some authors have criticized the meta-analyses, noting the lack of equivalence between preparations and inadequate definition or characterization of active principles in the trials, which seriously limits the clinical conclusions that can be drawn from the majority of trials to date. ^5,6Epidemiological studies of the cancer-protective effects of garlic consumption have also been subject to meta-analysis, and positive effects were found for stomach and colon cancers from raw and cooked garlic consumption. ^7,8
Garlic has not been official in the U.S. Pharmacopoeia since 1900, but it is listed in the 2002 edition of the National Formulary as “fresh or dried compound bulbs containing not less than 0.5% alliin.” The German Commission E approved the use of “fresh or carefully dried bulbs” as “supportive to dietary measures at elevated levels of lipids in the blood” and as a “preventative for age-dependent vascular changes.” ⁹ The European Scientific Cooperative on Phytotherapy (ESCOP) monograph indicates garlic for “treatment of elevated blood lipid levels insufficiently influenced by diet” and mentions the traditional indication for upper respiratory tract infections and catarrhal conditions while also noting that these lack trial support. ¹⁰ The World Health Organization (WHO) also includes mild hypertension as an indication. ¹¹ Both ESCOP and McKenna et al. ¹² provide comprehensive reviews of the recent scientific literature.
Historical/Ethnomedicine Precedent
In Europe, garlic has been used for millenia. It was a staple of the Roman army, Pliny recorded more than 60 uses for garlic, and Galen first recorded its use as a disinfectant before and after surgery. More recent folk use centers on respiratory conditions, including coughs, colds, flus, sinus and bronchial infections, pneumonia and tuberculosis, and the elimination of worms and other parasites. As an external treatment, garlic has been used as a “counterirritant” for rheumatic and arthritic conditions, as well as for earache, skin infections, and snakebites. Topical applications are also used in respiratory conditions. Garlic has been employed in all major world systems of medicine for many years. In China, garlic use was recorded in texts from the fifth centuryCE, principally as an antidote for poisons as well as a treatment for infectious and parasitical intestinal conditions such as diarrhea, dysentery, and diphtheria.
Known or Potential Therapeutic Uses
Antimicrobial, antifungal, atherosclerosis, bronchial and upper respiratory conditions, catarrh, colds, coughs, flu, gastric and colon carcinomas (prevention), hyperlipidemia, hypertension, hyperviscosity, immunostimulation, peripheral arterial occlusive disease, rhinitis, sinusitis, thrombosis.
Key Constituents
Organosulfur compounds (OSCs), principally alliin [(+)- S-allyl-L-cysteine sulfoxide] and gamma-L-glutamyl peptides. Alliin is transformed into allicin by allinase, and depending on physicochemical conditions, various derivatives may be formed. Flavonoids and saponins are also present.
Therapeutic Dosing Range
- Fresh Garlic: 2.7 to 4.0 g daily.
- Dried Powder: 0.4 to 1.2 g daily.
- Tincture (1:5): 20 mL daily.
- Oil: 2 to 5 mg daily.
- Standardized Extracts:
  - Garlic powder (Kwai): 200 to 300 mg three times daily.
  - Aged garlic extract (AGE, Kyolic): 300 to 800 mg three times daily.
  - Other preparations: Corresponding to 4 to 12 mg alliin, or 2 to 5 mg allicin-equivalent daily.

interactions review

Strategic Considerations

The German Commission E did not list any known interactions for garlic in its 1998 monograph. ⁹ However, the later monographs by WHO and ESCOP both list a possible interaction between garlic and warfarin. ^10,11Although garlic consumption is usually assumed to be a risk to anticoagulated patients, reliable reports of such interactions are not available. ¹³

As with ginkgo, garlic and several of its constituents have established antiplatelet activity in vitro. Using aggregometry in response to platelet-stimulating factors such as collagen and adenosine diphosphate (ADP), three clinical trials have demonstrated modest effects on platelet aggregation in vivo by AGE extracts ^14,15and garlic powder. ^16,17Bleed times and international normalized ratio (INR) were not measured, and the clinical significance of the antiaggregatory effects of garlic remains to be established. Three reports associate garlic alone with spontaneous bleeding, but none of these allows causality to be attributed to the herb ^18-20(see later discussion on garlic and antiplatelet thromboprophylactics). Cessation of high levels of garlic consumption before elective surgery may be prudent, but on the basis of currently available evidence, the risk of garlic-induced bleeding and interactions with drugs affecting hemostasis appears to be very low. ²¹

On the other hand, inclusion of garlic in protocols for patients at risk of thrombosis, particularly those with history of atherosclerotic disease, offers multiple “collateral” benefits due to the pleiotropic actions of the herb on several cardiac risk factors. ^22-27The lipid-lowering effect of garlic extracts operates by several mechanisms, including the inactivation of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. This has led at least one author to suggest the potential value of combining garlic with pharmaceutical HMG-CoA reductase inhibitors for hyperlipidemia to reduce the risk of adverse effects such as rhabdomyolysis in sensitive populations, such as renal transplant patients. ²⁸ This potentially beneficial interaction is proposed later, although previously undefined in the literature.

Effects on Drug Metabolism and Bioavailability

Experimental, animal, in vitro, and ex vivo human data suggest that garlic OSCs may be substrates, inducers, and/or inhibitors of various CYP450 enzymes. As with the pharmacodynamic effects of garlic, there are differences in effect among the different OSCs, different dose/duration regimens, and different species (mouse, rat, rabbit, human). The full spectrum of effects of OSCs on drug metabolism in humans is not well understood, but in vivo evidence is compelling for an inhibition of CYP450 2E1 by OSCs.

Diallyl sulfide (DAS) is converted by CYP2E1 to diallyl sulfoxide (DASO) and sequentially to diallyl sulfone (DASO2). ²⁹ These derivatives are competitive inhibitors of 2E1, and DASO2is also an irreversible (suicide) inhibitor of 2E1. ^30,31This is a typical example of 2E1 activity, which shares with CYP450 1A1 and 1A2 the role of metabolizing potentially carcinogenic aromatic hydrocarbons, and which may also bioactivate certain substrates to toxic or reactive intermediates (e.g., acetaminophen; see later discussion). ^32,33Loizou and Cocker ³⁴ found that both DAS and garlic oil extract showed significant inhibition of 2E1 in eight healthy human volunteers with the 2E1 probe chlorzoxazone. Gurley et al. ³⁵ also found significant inhibition of 2E1 after 28 days of garlic oil administration in healthy human volunteers using the same chlorzoxazone probe methodology. Davenport and Wargovich ³⁶ found that single-dose in vivo OSCs in a rodent model decreased 2E1 protein but not its messenger ribonucleic acid (mRNA) levels. They also noted a slight increase in 1A1 and 1A2 levels.

Inhibition of CYP450 2E1 is considered one of the major mechanisms by which garlic consumption reduces mutagenesis and carcinogenesis and exerts hepatoprotective effects. ^37,38Other mechanisms may be involved, including OSC induction of glutathione transferases as well as scavenging of carcinogenic free-radical species. ^39,40Recent studies suggest that a number of complex effects on signal-transduction pathways may be involved in the chemopreventive effects of garlic OSCs. ⁴¹ Garlic-drug interactions with 2E1 substrates caused by inhibition by garlic OSCs have not yet appeared to be a clinically significant issue, and case reports are lacking. Drug substrates that theoretically may be affected by inhibition of 2E1 are verapamil, the halogenated anesthetics, and (a minor pathway) theophylline. In a clinical study restricted to older volunteers (mean age, 67 years), Gurley et al. ⁴² found a 22% inhibition of 2E1 by garlic oil administered for 28 days. The authors suggested that age-related changes in CYP450 activity are significant and should be factored into drug dose and potential interactions calculations.

Garlic is not the only dietary substance to modulate 2E1 expression. Inducers include ethanol, lettuce, and above all, increased body weight or obesity, whereas inhibitors include watercress and elements of Camellia sinensis (both green tea and black tea), especially epigallocatechin-3-gallate. If polymorphisms are taken into account, the total contribution of these variables to individual response variation in 2E1-mediated clearance of the probe substrate chlorzoxazone is 73%, with body weight alone accounting for 43% of the phenotypical variability in 2E1 activity. ^43,44

The effect of garlic on CYP450 enzymes other than 2E1 is less clear. A “before and after” probe study with healthy volunteers examined the effect of Kwai (aged) garlic consumption (600 mg three times daily for 14 days) on probe drugs for CYP3A4 (alprazolam) and CYP2D6 (dextromethorphan) pharmacokinetics and found no significant effects after garlic administration. ⁴⁵ The authors concluded that aged (Kwai) garlic is unlikely to cause 3A4-modulated or 2D6-modulated drug interactions. Gurley et al. ³⁵ found no effect of garlic oil on 3A4, 2D6, or 1A2 in healthy volunteers using a midazolam, debrisoquin, and caffeine cocktail in the study previously mentioned that demonstrated 2E1 inhibition.

Foster et al. ⁴⁶ conducted an in vitro study using recombinant human CYP450 enzymes that investigated the effects of 10 different garlic products (including aged, odorless, oil, freeze-dried, and three fresh forms: common, Chinese, and elephant) on enzyme activity. The authors found that 2D6 was unaffected, but that 2C9^*1, 2C19, 3A4, 3A5, and 3A7 were all inhibited by fresh garlic, whereas 2C9^*2 was actively stimulated by fresh garlic. These authors concluded that pharmacokinetic interactions with narrow-therapeutic-range drugs may result from garlic consumption, affecting metabolism of drug substrates mediated by 2C9, 2D6, and 3A4. The same extracts were tested against an in vitro model of P-glycoprotein (P-gp) based on an adenosinetriphosphatase (ATPase) colorimetric assay, using verapamil as a positive control. (Stimulation of the ATPase assay is correlated with increased inhibitory activity of P-gps.) Aqueous extracts of aged garlic preparations exerted a very low to moderate inhibition of P-gp in the assay used. ⁴⁶ In another in vitro model based on human KB-C2 cells, Nabekura et al. ⁴⁷ found no effect of OSCs on the P-gp–mediated transport of daunorubicin and rhodamine 123. Greenblatt et al. ⁴⁸ used an in vitro human hepatocyte model to test possible activity of different water-soluble compounds in garlic for CYP inhibitory activity and found negligible effect, except for high concentrations (100 µmol/L) of S-methyl-L-cysteine and S-allyl-L-cysteine, both of which produced modest inhibition of CYP3A. The authors concluded that CYP3A interactions with garlic and prescription drugs were unlikely.

Pharmacokinetic data for garlic (other than those related to drug-metabolizing systems) are minimal. However, one rodent study examined the effect of the saponin constituents of garlic and concluded that these compounds may contribute to the lipid-lowering activity of garlic by reducing lipid absorption levels at the intestinal wall. ⁴⁹ Studies are required to delineate human pharmacokinetics of garlic and OSC preparations in order to determine the extent to which many of the important effects of OSCs described in vitro in animal models can be replicated in vivo at micromolar concentrations that correspond to those employed in the experimental models. Further research is also required to establish the full spectrum of effects of different forms of garlic and OSCs on drug metabolism and potential pharmacokinetic interactions. Inconclusive data are available relating to garlic and the human immunodeficiency virus type 1 (HIV-1) protease inhibitors, saquinavir and ritonavir (discussed later). Patients with HIV infection are likely to take garlic products or preparations, and physicians specializing in this patient population are usually aware of the complexities of managing polypharmaceutical regimens and empirically monitoring possible interactions. Other than this clinically circumscribed area, currently no compelling data exist on adverse pharmacokinetic interactions between pharmaceuticals and garlic preparations. The established inhibition of CYP450 2E1 underlies a major part of the hepatoprotective and chemoprotective benefits of garlic consumption.

herb-drug interactions

Acetaminophen

Effect and Mechanism of Action

This is primarily a pharmacokinetic interaction, whereby garlic extracts inhibit the CYP450 2E1 isoform that mediates the production of the hepatotoxic metabolite of acetaminophen (NAPQI). Although experimentally validated, the clinical significance of the interaction is not established.

Research

Acetaminophen is extensively metabolized through glucuronidation and sulfation as well as oxidation by CYP450 1A2, 3A4, and 1E2. ^50-52 Oxidative metabolism by 2E1 forms the reactive intermediate NAPQI ( N-acetyl- p-benzoquinone imine), which is subsequently conjugated by glutathione. Under normal circumstances, little NAPQI is formed, but if 2E1 undergoes induction, typically by alcohol consumption, NAPQI may be formed in greater-than-usual quantities. In turn, if glutathione capacity is exceeded at the same time, clinical hepatoxicity may result, with significant risk of fulminant hepatic failure. Deliberate overdose with acetaminophen is the major cause of drug-related liver failure and emergency liver transplants in the United States and until recently in the United Kingdom (when measures to restrict OTC availability of the drug were implemented). ^53,54 Emergency treatment of acetaminophen poisoning with N-acetylcysteine (NAC) can help regenerate glutathione stores and prevent further NAPQI formation, but NAC is usually effective only in the earliest stages of intoxication.

Extensive in vitro and in vivo evidence exists for the ability of garlic preparations in the form of fresh garlic, garlic oil, and AGE to inhibit human CYP450 2E1 ^30,35,46 (see also pharmacokinetics earlier). A number of rodent studies have established that pretreatment with different garlic preparations exerts a protective effect against single-dose–induced acetaminophen toxicity according to a number of endpoints, including hepatic histology, aminotransferase and lactate dehydrogenase levels, 2E1 levels, reduced glutathione levels, and cataracts. ⁵⁵ Studies have been performed with ajoene, ⁵⁶ S-allylmercaptocysteine (SAMC), ^57,58 DAS and fresh garlic, ^37,39 DASO ² , ⁵⁹ and diallyl disulfide (DADS) ⁶⁰ and garlic oil. ⁶¹ Although the animal evidence appears substantial, doses in these experimental studies are often high, from 5 g/kg body weight for fresh garlic extracts to between 25 and 200 mg/kg for isolated OSCs. These do not translate into typical dietary doses of garlic or normal supplemental or therapeutic intake using garlic extracts.

The only available human study, conducted by Gwilt et al., ⁶² examined the effects of 3 months’ pretreatment with AGE at a dose equivalent to six to seven cloves of garlic daily in healthy volunteers. A 1-g dose of acetaminophen was given before garlic treatment, and at the end of each month for 3 months, urinary and plasma measurements levels of acetaminophen and its conjugates were taken. A slight increase in sulfate conjugates was found, but no significant reduction in acetaminophen or its metabolites was noted. This study did not directly examine toxic doses of acetaminophen, but rather was seeking to determine effects of garlic on subtoxic levels of the drug, which may be different from effects at higher exposure levels.

Further human studies are required to establish whether the data from rodent experiments can be extrapolated to clinical practice.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Despite the experimental demonstration of garlic-acetaminophen interaction in animal models and the known inhibition of CYP450 2E1 in humans by garlic OSCs, garlic's clinical and therapeutic significance is not established. Disulfiram, a pharmaceutical inhibitor of 2E1, has been shown to reduce the formation of NAPQI in healthy volunteers pretreated with a single dose, 10 hours before receiving 500 mg acetaminophen toxicity from overdose or from chronic alcohol consumption. ⁵⁰ In the study previously described, Gwilt et al. ⁶² failed to find similar effects exerted by garlic in healthy volunteers. Given that acetaminophen poisoning is a serious condition requiring intensivist management, garlic use as an acute management strategy would be inappropriate in this context. For alcoholic patients with any degree of compliance, however, the addition of garlic by diet or supplementation would appear to be a logical counter to the chronic effects of alcohol on 2E1 induction.

Dipyridamole and Related Antiplatelet Thromboprophylactics

Evidence: Dipyridamole (Permole, Persantine).

Extrapolated, based on similar properties: Antiplatelet thromboprophylactics: Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline, Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult Chewable Aspirin, ZORprin); combination drugs: ASA and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); ASA, codeine, and carisoprodol (Soma Compound with Codeine); ASA and codeine (Empirin with Codeine); ASA, codeine, butalbital, and caffeine (Fiorinal); cilostazol (Pletal), clopidogrel (Plavix), ticlopidine (Ticlid); combination drug: ASA and extended-release dipyridamole (Aggrenox, Asasantin).

	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity or
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

Garlic extracts and OSC compounds have established antiaggregatory effects. Coadministration of garlic with dipyridamole results in synergistically increased antiplatelet effects. Although related antiplatelet agents may operate through different mechanisms, net disabling of platelets is likely to be increased. Professional monitoring and management of this theoretical additive interaction are required.

Research

A number of in vitro and animal experiments suggest that garlic and certain garlic OSCs, particularly ajoene, exert significant antiplatelet activity through a variety of routes, including inhibition of ADP-induced aggregation. ^63-70 Multiple mechanisms are involved and include membrane fluidity changes, inhibition of phospholipase C, inhibition of calcium mobilization, increase in nitric oxide and cyclic adenosine monophosphate (cAMP) production, and inhibition of thromboxane A ² (TXA ² ), all of which are antiaggregatory in effect. ^71,72 Human studies have demonstrated antiaggregatory and antithrombotic activity in vivo with various forms of garlic, in healthy individuals as well as patients with atherosclerotic disease. ^{15-17,63,67,73-75}

Apitz-Castro et al. ⁷⁶ employed ajoene, a garlic OSC found in oil preparations but not in AGE or powdered garlic, in an aggregometric investigation of the effects of the garlic compound on collagen-evoked platelet aggregation on the blood of healthy volunteers. The investigators also examined the effects of indomethacin, dipyridamole, and forskolin alone, as well as in combination with the ajoene. The effects of coadministration were found to be a synergistic (i.e., greater than additive) increase in aggregation for the combinations. In the case of dipyridamole, the median inhibiting dose ID ⁵⁰ was decreased fourfold with garlic. Harenberg et al. ⁷⁷ found that although fibrinolysis increased after 4 weeks of garlic consumption in healthy volunteers, collagen-evoked and ADP-evoked aggregation remained unchanged.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Dipyridamole is primarily used in conjunction with coumarin anticoagulants in cardiac valve replacement patients and seldom used as a primary antiplatelet drug, compared with the commonplace “baby aspirin” or clopidogrel, as well as the emerging oral glycoprotein IIb/IIIa receptor–binding drugs. Although direct clinical data on the interaction are lacking for most antiplatelet agents, extrapolation appears warranted by the existing pharmacological data. Determination of context will define whether coadministration should be adopted or avoided within specific patient populations. For example, within an integrative therapeutic context, hyperlipidemic patients with or without a history of thrombosis or coronary artery disease (CAD) would benefit from addition of garlic consumption, with monitoring of the levels of coadministered antiplatelet pharmaceuticals and close attention to symptoms, including peripheral bleeds and INR increases. Patients at risk of thromboembolism invariably receive several drugs in combination to achieve anticoagulation and thromboprophylaxis. With professional management, the addition of garlic to these regimens may improve overall outcomes, as well as enable lower doses of the drugs, which may decrease the likelihood of adverse drug effects. ^78,79

Doxorubicin and Related Anthracycline Chemotherapy Agents

Effect and Mechanism of Action

Anthracyclines generate free radicals that cause oxidative damage, particularly microsomal lipid peroxidation, through an iron-dependent process, which results in cardiotoxicity and adverse effects on other tissues, distinct from their antitumor actions. Garlic extracts exert a protective effect against cardiotoxicity from doxorubicin by specific enhancement of endogenous myocardial antioxidants and possibly by additional, unknown mechanisms. The interaction has been demonstrated in animal experiments; clinical studies and reports are unavailable to date.

Note: Cardiotoxicity is similar between equipotent doses of doxorubicin and daunorubicin, slightly lower for epirubicin, and only one-sixth that of doxorubicin for equipotent doses of mitoxantrone. Doxil (liposome-encapsulated doxorubicin) has negligible cardiotoxicity, presumably because of negligible cardiac exposure to the active drug with the pharmacokinetics of the liposome-encapsulated preparation.

Research

Doxorubicin is a highly effective antineoplastic agent, but acute and chronic cardiotoxicity is an adverse effect occurring in up to one third of the patients treated after a cumulative dose of 300 mg/m ² , and increasing sharply beyond a cumulative dose of 360 mg/m ² . The resultant irreversible and dose-dependent cardiomyopathy limits its clinical usefulness. The chronic form of anthracycline-induced cardiotoxicity may only manifest years after initial exposure, after an apparently asymptomatic interval, and has been documented two decades after treatment. ⁸⁰ Cardiotoxicity of anthracycline chemotherapy agents is multifactorial and partly involves oxidative stress mediated by an iron-catalyzed Fenton reaction; iron-chelating agents such as dexrazoxane have been shown to decrease doxorubicin cardiac toxicity. The mechanisms of cardiotoxicity are considered to be distinct from the tumoricidal activity of the compounds. ⁸¹

Several animal studies have examined the effects of garlic and OSCs on doxorubicin-induced cardiotoxicity. Intraperitoneal administrations of AGE ⁸² and DADS ⁸³ were found to exert cardioprotective effects. Oral doses of garlic extracts (20 and 100 mg/kg) induced significant changes in the redox status of mouse red blood cells (measured by MDA generation and glutathione peroxidase activity) after doxorubicin exposure. ⁸⁴ Mukherjee et al. ⁸⁵ used fresh garlic homogenate administered to rats at oral does of 250 and 500 mg/kg daily for 30 days, followed by a single dose of Adriamycin, 30 mg/kg. Cardiotoxicity was reduced according to histopathological criteria. In addition, myocardial redox enzyme activity (catalase, superoxide dismutase, glutathione peroxidase) was increased, and tumor necrosis factor alpha (TNF-α) expression was reduced.

These experimental studies provide preliminary support for the potential interaction, but it remains to be established whether oral doses of garlic extracts or purified OSCs in humans can generate sufficient concentrations in vivo to correspond to the micromolar levels employed in the in vitro and animal models. Research into garlic and OSC pharmacokinetics in vivo is required to establish dose parameters for the interaction in clinical practice. Nonetheless, the multifactorial antioxidant effects of garlic are being increasingly understood, with extensive implications for inflammatory and cardiovascular diseases as well as cancer. ^41,86

Integrative Therapeutics, Clinical Concerns, and Adaptations

Acute cardiotoxicity can be evaluated by creatine kinase, particularly the cardiac specific MB isoenzyme. Chronic cardiotoxicity can be monitored using electrocardiography and left ventricular performance monitored by computerized M-mode echocardiography measuring the ejection fraction and/or MUGA scan (nuclear medicine technique for measuring cardiac ejection fraction), both of which are reliable and highly sensitive noninvasive parameters for evaluating myocardial contractility.

Anecdotal clinical experience has indicated that therapeutic benefit can be obtained in patients with existing doxorubicin-induced cardiomyopathy and clinical congestive heart failure using L-carnitine, coenzyme Q10, taurine, fish oil, magnesium, and hawthorn (Crataegus)leaf/flower and berry extracts, at least in some cases. Given the additional pluripotent effects of garlic OSCs on signal transduction in cancer cells, including cell cycle arrest, induction of apoptosis, and inhibition of inflammatory cytokines, as well as inhibition of multidrug (P-gp) resistance, there would appear to be good grounds for incorporating garlic extracts into prechemotherapy protocols for prophylaxis of anthracycline-induced cardiotoxicity. ^41,87,88 Integrative management with these nutrients, botanicals, and appropriate pharmaceuticals may be of greatest clinical benefit, when applied by health care professionals trained and experienced in both nutritional therapeutics and conventional medicine. Randomized controlled clinical trials in this area would be of great interest.

Hydroxymethylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors (Statins)

Effect and Mechanism of Action

The mechanism of garlic-induced hypocholesterolemic activity is multifactorial but includes inhibition of cholesterol synthesis at the level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Coadministration of garlic with pharmaceutical HMG-CoA reductase inhibitors may enable lower statin drug doses, resulting in reduced risk of drug-related adverse effects.

Research

The pharmacology of garlic's cholesterol-lowering action is multifactorial, and remains to be fully characterized. ⁸⁹ In vitro studies with rodent and human hepatocyte models of cholesterol synthesis have demonstrated that HMG-CoA reductase inhibition is a significant but not the sole mechanism. ^90-93 More recent data implicate inhibition of sterol-4α-methyl oxidase as being the major enzyme involved. ⁹⁴

Integrative Therapeutics, Clinical Concerns, and Adaptations

Although efficacy has been established by numerous clinical trials, the magnitude and clinical significance of the hypocholesterolemic effects of garlic extracts are controversial, according to meta-analyses of the available trial data. ^1,3,95 In clinical practice, however, incorporation of garlic and garlic extracts into integrative hypolipidemic protocols with a variety of nutritional and botanical agents is commonplace. The increasingly widespread prescription of HMG-CoA reductase inhibitors by primary health care providers for relatively moderate cholesterol elevations (or previously normal-range values) has raised concerns about the potential long-term effects of depletion of coenzyme Q10 by these agents, particularly in populations with history of serious CAD and myocardial infarction. ⁹⁶ Degree of coenzyme Q10 depletion by statins depends on several factors, including patient age, but a positive correlation exists between level of dosage and level of depletion (see Coenzyme Q10 monograph).

For patients experiencing adverse effects of statin drug therapy, such as myalgias and fatigue, it is possible that drug dose levels may be lowered without loss of efficacy by combination with garlic. For patients with a previous history of cardiac disease also prescribed statin therapy, prudence would suggest that prophylaxis of cardiomyopathy should not only include coadministration of coenzyme Q10 to appropriate levels, but also incorporate integrative hypocholesterolemic protocols that may allow exposure levels to statins to be lowered or, in some cases, the drug to be replaced by nonpharmaceutical interventions. Other groups at specific risk, such as renal allografts, may also be considered for this approach. ²⁸

Mucositis-Inducing Chemotherapeutic Agents, Including Fluorouracil, Bleomycin, Doxorubicin, and Ethanol

Effect and Mechanism of Action

Mucositis (oral and intestinal) can be a dose-limiting adverse effect of certain chemotherapies. Preliminary evidence suggests that garlic extracts may exert a protective activity at the mucosa, which may reduce mucositis and increase ability to sustain required doses of chemotherapy. The clinical significance of the interaction remains to be established. A possible ulceroprotective effect against ethanol-induced gastropathy has been noted, which may be considered a related interaction.

Research

Garlic and OSCs are known to have antioxidant and anti-inflammatory effects. Recent evidence has indicated garlic modulates of inflammatory cytokines in various tissues, including intestinal epithelia. Spontaneous secretion of TNF-α in Caco-2 cells was inhibited by allicin, which also suppressed interleukin-8 (IL-8) and interleukin-1 (IL-1), while inhibiting degradation of INF-κ (thus increasing NF-κ inhibition). ⁹⁷ Together with multiple effects of OSCs on redox status and eicosanoid metabolism, several plausible mechanisms underlie the potential protective effects against chemotherapy-induced mucositis, as demonstrated in animal models for both methotrexate and 5-FU using dietary AGE. ^98,99 Related oxidative mechanisms are involved in ethanol-induced gastric ulceration. Another rodent study observed that an oral garlic oil preparation (0.25 and 0.5 mg/kg) administered 30 minutes before ingestion of ethanol (1 mL) reduced the ulcer index, increased antioxidant enzyme levels, and reduced lipid peroxidation compared with controls. ¹⁰⁰ Extrapolation from these studies to in vivo human oral consumption ultimately depends on a fuller understanding of OSC pharmacokinetics than is currently available.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Treatment of chemotherapy- or radiation-induced mucositis (oral and intestinal) is particularly amenable to integrative strategies employing combinations of botanicals agents (see also Aloe and Licorice Root monographs) and nutrients such as glutamine, vitamin E, and beta-carotene. Combination protocols are often used in integrative oncology environments, despite the lack of published trial support at present. The possible inclusion of garlic/OSC extracts in such protocols is an interesting possibility because similar to capsicum, the herb is popularly considered to have a gastroirritant potential, and as with capsaicin, garlic in fact can exert gastroprotective effects. Additionally, garlic OSCs interact with a number of molecular targets with a resultant anticancer action. At present the optimal form and dose of garlic extracts in any such protocol need to be established empirically; ultimately, clinical trials are required to establish the benefits of adding garlic for treatment of chemotherapy-related mucositis.

Saquinavir and Related Antiretroviral Protease Inhibitors

Effect and Mechanism of Action

Saquinavir, like all protease inhibitors, is a cosubstrate of CYP3A4 and P-gp. A pharmacokinetic interaction has been demonstrated in healthy volunteers, in whom garlic significantly reduced drug bioavailability. Further data are needed to establish the precise mechanism and clinical significance before extrapolations to other antiretrovirals and to HIV-1 patient populations are fully warranted.

Research

Piscitelli et al. ¹⁰¹ administered garlic extracts, with an allicin content equivalent to four to six garlic cloves per day, to 10 healthy volunteers for 3 weeks. Before and after the garlic treatment period, saquinavir was administered for 3 days (1200 mg three times daily), and blood samples were taken to measure pharmacokinetic parameters. After a 10-day washout period, the saquinavir dose was repeated and a further sample measured. Peak concentration and AUC (area under curve) of saquinavir were reduced by 54% and 51%, respectively, and after the washout period, levels did not return to baseline but were approximately 60% to 70% of the pretreatment values. The authors suggested that either induction of intestinal 3A4 reduced the bioavailability or P-gp may be involved, rather than changes in systemic clearance. Failure to return to baseline levels after the washout period is unexplained. A further finding that complicates interpretation of this study was the separation of the small number of subjects into two distinct groups. The first group had no significant change in saquinavir AUC with garlic, but exhibited a drop in AUC after the washout period. The other group had a significant drop in saquinavir AUC with garlic, but postwashout AUC was less than baseline. This bimodal pharmacokinetic result awaits a satisfactory explanation.

Garlic administration does not significantly affect the single-dose pharmacokinetics of the related protease inhibitor ritonavir in healthy volunteers after 4 days of acute dosing with garlic, according to a study by Gallicano et al. ¹⁰² However, the dose of garlic in this study was relatively low (10-mg odorless capsules daily), and a trend was noted to decreased bioavailability. Ritonavir powerfully inhibits and induces CYP3A4, and a single dose cannot be extrapolated to steady-state kinetics of therapeutic administration. Available experimental studies implicate both P-gp and intestinal 3A4 in ritonavir and saquinavir clearance modulation. An in vitro investigation using a MDR1-transfected MDCK cell model for assaying P-gp efflux activity found that allicin inhibited P-gp–mediated efflux of ritonavir in a dose-dependent fashion. ¹⁰³ Mouly et al. ¹⁰⁴ used another in vitro model, the Caco-2 cell, to examine the kinetics of saquinavir in relation to 3A4, P-gp, and serum protein binding and implicated both 3A4 and P-gp, but not serum albumin, in saquinavir availability.

Case reports are lacking.

Clinical Implications and Adaptations

Patients with HIV/AIDS are likely to use garlic preparations. Such use, if self-prescribed, should be disclosed to the prescribing physician or specialist team managing the patient's drug regimen. However, blanket cautions regarding dangers of herbal modulation of antiviral drug therapy for HIV patients are arguably inappropriate, although frequently made in the literature. It is well known that long-term retroviral agents in HIV-infected patients exhibit kinetic differences that are not necessarily revealed by short-term studies in healthy volunteers. Both saquinavir and ritonavir are known to exhibit decreases in AUC over several months of administration in infected patients. ¹⁰⁵ The interactivity of the antiretroviral drugs with each other and with unrelated drugs is well known among HIV/AIDS specialist providers and most patients. Polypharmacy is common, and viral load is invariably monitored as an indicator of antiviral therapeutic efficacy. Serum drug levels should be monitored directly; serum dosage, timing of administration, and drug combinations may need to be adjusted accordingly and frequently. (See also St. John's Wort monograph, Indinavir section.)

Effect and Mechanism of Action

A theoretical additive effect between coumarin anticoagulants and garlic upon hemostasis is hypothesized to increase INR and/or increase risk of bleeding. Reliable reports of the interaction are unavailable, and direct pharmacodynamic interaction is contradicted by the clinical data.

Research

Substantial data suggest that garlic and OSC components of garlic exert in vitro and in vivo antiaggregatory effects (see Antiplatelet Thromboprophylactics earlier). However, data demonstrating effects of garlic on coagulation proper (i.e., secondary hemostasis), through interference with the production or action of soluble coagulation factors, are unavailable.

Reports of bleeding induced by garlic alone are rare, and of the three reports available, none appears to demonstrate a causal link between garlic consumption and hemorrhagic episodes. Spontaneous spinal epidural hematoma in an 87-year-old man who consumed an average of four garlic cloves daily for an unstated duration was attributed to garlic. ¹⁹ In their review of the evidence for interactions between warfarin and garlic, however, Vaes and Chyka ¹³ noted that such epidural hematomas are rare, and the cause is unknown in 40% of cases. ¹³ Another anecdotal report involved postoperative bleeding following mammoplasty; atypical “bloody oozing” was noted during surgery, and a 200-mL hematoma developed postoperatively and was later evacuated. The patient had apparently had a “heavy garlic intake” preoperatively, although preparation, dose, and duration of intake were not specified. At a second, later mammoplasty, after discontinuation of garlic, the bleeding did not recur. ²⁰ A third case involved a 72-year-old man who experienced postoperative hemorrhage after a standard transurethral prostate resection procedure. He required transfusion with 4 units of blood. The patient later admitted habitual garlic consumption, the preparation and dose of which were not stated. ¹⁸

A warfarin-garlic interaction is suggested by authoritative secondary sources, such as the ESCOP ¹⁰ and WHO ¹¹ therapeutic monographs, both of which base this claim on a single anecdotal report by Sunter in 1991. The report underlying this apparent interaction was a short letter from Sunter containing inadequate information that failed to mention the form, preparation, dose, duration of administration, comedications, or case history details, or even the magnitude of the apparent INR change. ¹⁰⁶ This report has been challenged as “unreliable,” scoring zero in the scale of report reliability devised by Fugh-Berman and Ernst. ¹⁰⁷ Meanwhile, unsupported claims that garlic prolongs INR are repeated by derivative sources without substantiation. ¹⁰⁸ A controlled trial using AGE at 1200 mg/day for 4 weeks versus placebo in eight patients, all stable taking warfarin, found no significant changes between garlic and placebo when INR was compared to baseline levels after garlic administration. ¹⁰⁹ Another trial with 48 patients monitored potential bleeding and thromboembolic episodes during anticoagulant therapy with warfarin while consuming AGE at 5 mL twice daily for 12 weeks. No adverse events or changes in hemostatic or platelet parameters were noted. ²¹

Reports

Pathak et al. ¹¹⁰ reported a case in which garlic tablets consumed at 600 mg/day for 12 days apparently reduced the INR of an 82-year-old patient previously stable taking fluindione. The case reporting seems reliable, and the report is somewhat unexpected because fluindione is an indanedione derivative similar to phenindione, which is used as vitamin K antagonist anticoagulant, mainly in France. Cessation of garlic tablets restored the INR within 4 days. The authors suggested a possible pharmacokinetic induction by garlic compounds of the CYP450 enzymes responsible for metabolizing the drug, or a possible effect on serum protein binding. ¹¹⁰ Assessment of the case is problematic; fluindione is known to exhibit extreme individual variation in pharmacokinetics, and the pathways of its metabolism are not definitely established. ¹¹¹

Clinical Implications and Adaptations

The 4-hydroxycoumarin compound warfarin is the most widely used anticoagulant drug in the Western world. It is known for a high variability in interindividual and intraindividual response. The primary individual factors affecting response variability are age and polymorphisms of CYP450 2C9. ¹¹² The incidence of warfarin-related bleeding complications is difficult to estimate because of methodological issues surrounding data collection and interpretation. Recent calculations suggest that improved anticoagulation control has reduced the serious adverse drug reaction (ADR) category of “major bleeds, non-fatal” incidence to approximately 2.5% to 8.0%, with a “minor bleed” incidence of about 15% per year. Fatal bleed estimates vary from 1% to 4.8% per year. ¹¹³ Warfarin interacts with a wide range of drugs, including antibiotics, central nervous system agents, and cardiac drugs, as well as many dietary ingredients, most of which increase anticoagulation. ¹¹⁴

All this confounds the already-complex situation of determining the medical appropriateness, form, and level of anticoagulation, especially in older individuals with multiple risk factors for bleeding, such as unstable INR, comorbidities (especially bleeding related), polypharmacy (especially with NSAIDs), advanced age, and difficulty in compliance with requirements of coagulation control.

Synergistic or additive interaction between warfarin and garlic is effectively unproven. It has been well argued that anticoagulation and antithrombotic therapy exemplifies the methodological and theoretical limits that pervade the discussion of interactions in general; in particular, the development of more precise tools to test for potential interactions is needed. ^115,116 Meanwhile, candidates for garlic coadministration with warfarin might best be reviewed on a case-by-case basis before using garlic extracts, and if appropriate, they should be monitored for signs of increased peripheral bleeding after initiating coadministration.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Chlorzoxazone

Chlorzoxazone (Paraflex, Parafon Forte, Relaxazone, Remular-S).

Several pharmacokinetic studies examining the effect of garlic and its OSCs on CYP450 2E1 have used chlorzoxazone probe methodology (see Effects on Drug Metabolism and Bioavailability). Because a degree of 2E1 inhibition has been established by these studies, this finding is “reversed” by some authors into a presumed or purported interaction. However, the therapeutic index of chlorzoxazone is not such to warrant a particular caution, and in practice, drug dose levels and frequency of this antispasmodic are often adjusted to the required level of symptom relief. Given the lack of reports of the interaction and its likely minimal significance, it is currently classified here as “overstated.”

Isoproterenol

Isoproterenol (Isoprenaline; Isuprel, Medihaler-Iso).

The nonselective beta-adrenergic receptor agonist isoprenaline was originally used in inhalant form for asthma and parenterally for cardiac resuscitation. In most applications, it has now been replaced by more selectively acting agents. Coadministration of garlic with isoprenaline in animal models has shown that garlic may reduce the proarrhythmic adverse effects associated with the drug, as well as minimize or prevent ischemic and necrotic damage to the heart (and other organs) that can result from exposure to excessively high doses of the drug. ^117-119 Some secondary sources list this as an established interaction, based on the animal evidence. ¹²⁰ In everyday practice, the drug is little used, and in any event it is improbable that isoproterenol would be administered at doses that might induce necrotic organic toxicities. Of interest, however, are related animal studies that have demonstrated an antiarrhythmic activity in garlic extracts in experimentally induced models of ventricular and supraventricular arrhythmias. ^121-123

Oral Hypoglycemic Agents and Insulin

Buformin (Andromaco Gliporal, Buformina), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol; Glucotrol XL), glyburide (glibenclamide; Diabeta, Glynase, Glynase Prestab, Micronase, Pres Tab), insulin (animal-source insulin: Iletin; human analog insulin: Humanlog; human insulin: Humulin, Novolin, NovoRapid, Oralin), metformin (Dianben, Glucophage, Glucophage XR); combination drugs: glipizide and metformin (Metaglip), glyburide and metformin (Glucovance); tolazamide (Tolinase), phenformin (Debeone, Fenformin), tolbutamide (Orinase, Tol-Tab).

A handful of early studies conducted in the 1960s and 1970s suggested hypoglycemic activity in experimental or animal models, and these data have been used to suggest a speculative interaction with insulin. ^124,125 Of the few human investigations that examined blood sugar parameters in response to garlic or OSCs, most have failed to detect significant hypoglycemic activities resulting from garlic consumption, although some trials have noted trends toward lowered blood glucose levels. ^2,16,74 One study noted bimodal gender differences in glycemic responses to garlic, with females experiencing elevation and males reduction of blood sugar. ¹²⁶ Recent evidence suggests that garlic extracts may be protective against diabetes-induced sequelae by inhibiting glycation. ^127,128 Antioxidant cardioprotective and vasodilatory effects are also relevant in diabetic patients. However, significant reduction of blood glucose levels does not appear to be a viable therapeutic strategy in management of diabetes, and interactions with oral hypoglycemics would seem to be speculative based on current data.

Surgery

The literature contains two reports of postoperative bleeding purported to be associated with garlic use, as discussed earlier under Warfarin and related Oral Vitamin K Antagonist Anticoagulants. However, the data in both cases are inadequate to ascribe causality to the herb. Given the lack of reports of either spontaneous or postoperative bleeding associated with garlic use, it would appear that moderate garlic use is generally safe for those undergoing elective surgery. Preoperative measurement of bleed times or temporary cessation of garlic consumption may be prudent management strategies, depending on individual circumstances. It is axiomatic that herb and nutrient intake are disclosed before surgery; however, the general risk associated with garlic appears to be overstated in the secondary and derivative literature.

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91.Gebhardt R. Inhibition of cholesterol biosynthesis by a water-soluble garlic extract in primary cultures of rat hepatocytes. Arzneimittelforschung 1991;41:800-804.View Abstract
92.Liu L, Yeh YY. S-alk(en)yl cysteines of garlic inhibit cholesterol synthesis by deactivating HMG-CoA reductase in cultured rat hepatocytes. J Nutr 2002;132:1129-1134.View Abstract
93.Kumar RV, Banerji A, Kurup CK, Ramasarma T. The nature of inhibition of 3-hydroxy-3-methylglutaryl CoA reductase by garlic-derived diallyl disulfide. Biochim Biophys Acta 1991;1078:219-225.View Abstract
94.Singh DK, Porter TD. Inhibition of sterol 4α-methyl oxidase is the principal mechanism by which garlic decreases cholesterol synthesis. J Nutr 2006;136:759S-764S.View Abstract
95.Silagy CA, Neil HA. A meta-analysis of the effect of garlic on blood pressure. J Hypertens 1994;12:463-468.View Abstract
96.Langsjoen PH, Langsjoen AM. The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10: a review of animal and human publications. Biofactors 2003;18:101-111.View Abstract
97.Lang A, Lahav M, Sakhnini E et al. Allicin inhibits spontaneous and TNF-α induced secretion of proinflammatory cytokines and chemokines from intestinal epithelial cells. Clin Nutr 2004;23:1199-1208.View Abstract
98.Horie T, Matsumoto H, Kasagi M et al. Protective effect of aged garlic extract on the small intestinal damage of rats induced by methotrexate administration. Planta Med 1999;65:545-548.View Abstract
99.Horie T, Awazu S, Itakura Y, Fuwa T. Alleviation by garlic of antitumor drug-induced damage to the intestine. J Nutr 2001;131:1071S-1074S.View Abstract
100.Khosla P, Karan RS, Bhargava VK. Effect of garlic oil on ethanol induced gastric ulcers in rats. Phytother Res 2004;18:87-91.View Abstract
101.Piscitelli SC, Burstein AH, Welden N et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002;34:234-238.View Abstract
102.Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 2003;55:199-202.View Abstract
103.Patel J, Buddha B, Dey S et al. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: changes in P-gp and CYP3A4 activity. Am J Ther 2004;11:262-277.View Abstract
104.Mouly SJ, Paine MF, Watkins PB. Contributions of CYP3A4, P-glycoprotein, and serum protein binding to the intestinal first-pass extraction of saquinavir. J Pharmacol Exp Ther 2004;308:941-948.View Abstract
105.Gisolf EH, van Heeswijk RP, Hoetelmans RW, Danner SA. Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir. AIDS 2000;14:801-805.View Abstract
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108.Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-2211.View Abstract
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