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

Summary: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.