Garlic Flavonoids and Organosulfur Compounds: Impact on the Hepatic Pharmacokinetics of Saquinavir and Darunavir

Abstract

The therapeutic efficacy of saquinavir and darunavir is affected by the presence of xenobiotics (such as garlic compounds) capable of modifying transporter-enzyme interplay. To ascertain the mechanism of interactions between antiretroviral drugs and garlic supplements and to identify the garlic constituents responsible, the hepatic pharmacokinetics of two antiretroviral drugs was investigated in the presence of garlic phytochemicals and aged garlic extract. For this purpose, rat liver slices and isolated rat hepatocytes were used. Aged garlic extract significantly inhibited saquinavir efflux from rat hepatocytes, while the efflux of darunavir significantly increased. Phytochemicals inducing distribution changes of saquinavir and darunavir were most probably flavonoids and lipophilic organosulfur compounds, respectively. All tested phytochemicals (except S-allyl L-cysteine) and aged garlic extract inhibited CYP3A4 metabolism of both drugs and modulated hepatic distribution of the corresponding saquinavir and darunavir metabolites. The competition between saquinavir and garlic constituent(s) for the same binding site on the efflux transporter and the positive cooperative effect between darunavir and garlic phytochemical(s), which bind to separate binding places on transporter, are the most probable mechanisms explaining the plasma profile changes, which could occur in vivo during concomitant consumption of antiretrovirals and garlic supplements.

First-Pass Metabolism Changes After Long-Term Garlic Supplementation

“…Saq) from these transporters, causing an increase of intrahepatic Saq concentrations. The inhibition of CYP3A4 HIV-PI metabolism by AGE was also confirmed in that study (Berginc et al, 2010d). …”

HIV protease inhibitors: garlic supplements and first‐pass intestinal metabolism impact on the therapeutic efficacy

“…It has been speculated that pharmacokinetic interactions between Saq and garlic phytochemicals might be caused by the induction of efflux transporters and CYP3A4 [8], but these assumptions have not been confirmed and responsible garlic phytochemicals have not yet been identified. Recent studies in our laboratory indicated that aged garlic extract (AGE) [10] and individual AGE phytochemicals [11] could also exert significant short-term effects on transporter-enzyme (i.e. Pgp and CYP3A4) interplay.…”

“…Namely the activities of secretory (Pgp, MRP-2, breast cancer resistance protein -BCRP) and absorptive (proton dependent peptide transporter 1 -PepT1, Organic anion transporting polypeptide -OATP, monocarboxylic acid transporter 1 -MCT-1) intestinal transporters in rat small intestine and Caco-2 cell monolayers significantly changed in the presence of AGE on the luminal side of intestinal tissue and cells, and this resulted in significant permeability changes of drugs, prescribed for the management of cardiovascular conditions and diabetes [10]. Furthermore, S-allyl L-cysteine, the major organosulphur compound present in AGE, and other lipophilic organosulphur compounds (diallyl disulphide, allyl methyl sulphide) also significantly enhanced Pgp-mediated efflux and inhibited CYP3A4 metabolism, whereas flavonoids rutin, tangeretin, nobiletin and quercetin inhibited both; Pgp efflux and CYP3A4 metabolism [11].…”

Protective effect of grape seed and skin extract on high dosage garlic-induced renal oxidative stress

“…Garlic (Allium sativum L.) has been widely used in traditional medicine and its health effects are mainly attributable to organosulfur compounds (Berginc et al, 2010) and to flavonoids and phenolics (Shirzad et al, 2011). However, some controversies persist concerning garlic dose and mode of administration.…”

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Protective effect of grape seed and Protective effect of grape seed and Protective effect of grape seed and skin extract on high dosage garlic skin extract on high dosage garlic skin extract on high dosage garlic---induced renal oxidative stress induced renal oxidative stress induced renal oxidative stress

BJP

IntroductionGarlic (Allium sativum L.) has been widely used in traditional medicine and its health effects are mainly attributable to organosulfur compounds (Berginc et al, 2010) and to flavonoids and phenolics (Shirzad et al, 2011). However, some controversies persist concerning garlic dose and mode of administration.

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