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Abstract

Grant Number:	1R21AT002712-01
Project Title:	Garlic Metabolism and Cytochrome P450 Modulation

PI Information:	Name	Email	Title
	SHEN, DANNY D.	ds@u.washington.edu	PROFESSOR AND CHAIR OF PHARMACY

Abstract: DESCRIPTION (provided by applicant): Garlic supplements are widely used for the treatment of high blood cholesterol and lipids. Until recently, garlic supplements were thought to be well tolerated and relatively safe. Adverse interactions between garlic supplements and several narrow therapeutic drugs, including anticoagulants (warfarin, fuindione) and HIV protease inhibitors (saquinavir, ritonavir), have been reported within the past 2 years. Animal and in vitro studies with known organosulfur constituents of garlic, as well as garlic extracts, are known to simultaneously inhibit and induce several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa. However, very recent studies in human subjects have produced conflicting data as to the effects of garlic supplements on cytochrome P450 function. Our specific hypotheses are: 1) the effects of garlic supplements on CYP and Pgp function vary with the type of garlic preparation (viz. garlic powder, steamed-distilled garlic oil, and aged garlic); and 2) garlic's effect is time- and regimen-dependent (e.g. it acutely inhibits and chronically induces CYP3A4 and Pgp activities in human subjects). Two separate "cocktails" of CYP and Pgp probe substrates, including caffeine (1A2), buproprion (2B6), chlorzoxazone (2E1), tolbutamide (2C9), omeprazole (2C19), metoprolol (2D6), midazolam (3A4/5), and digoxin (Pgp), will be administered to a panel of healthy human volunteers at various times during and shortly after discontinuation of daily intake of garlic supplement. Pharmacokinetics of known bioactive garlic constituents and their biotransformation products will be simultaneously studied through collection of blood, breath and urine samples. Garlic metabolite data may offer clues as to which garlic-derived compounds may be responsible for the putative metabolic effects. Specifically, we will measure metabolites deriving from allicin and allylic sulfides, which are the main constituents of garlic powder and garlic oil. We will also measure metabolites of S-allylcysteine, which is derived from hydrolysis of allylic cysteinyl peptides in garlic powder and aged garlic. These metabolic studies in human subjects will be conducted at the University of Washington General Clinical Research Center. The results will provide critical information for the design of further clinical studies to characterize and elucidate potentially important adverse garlic-drug interactions.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
P glycoprotein, angiosperm, cytochrome P450, dietary supplement, physical chemical interaction
drug interaction, drug metabolism, enzyme induction /repression, food processing /preparation, nutrient interaction, pharmacokinetics, physical state, plant extract, vegetable oil
alternative medicine, blood test, breath test, clinical research, human subject, nutrition related tag, urinalysis

Institution:	FRED HUTCHINSON CANCER RESEARCH CENTER
	BOX 19024, 1100 FAIRVIEW AVE N
	SEATTLE, WA 981091024
Fiscal Year:	2005
Department:
Project Start:	01-JUN-2005
Project End:	31-MAY-2008
ICD:	NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
IRG:	ZAT1

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