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The mid-1990s, HIV protease inhibitors (PIs) have been largely responsible for recent successful results in the treatment of HIV infected patients.1) A combination use of two kinds of reverse transcriptase inhibitors and an HIV protease inhibitor, highly active anti-retrovial therapy (HAART), has been found to be a better therapy than either drug alone in reducing HIV RNA levels and increasing CD4 cell counts. 2)On the other hand, a systematic review about alcohol use and HIV pharmacotherapy by Kresina et al. reported that alcohol consumption by persons infected with HIV is one of important medical management issues, because alcohol consumption is a risk factor for poor medication adherence and can modify liver drug metabolism.3) They also concluded that research areas that are of particular importance for HIV therapy is clarifying the relationships and interactions among alcohol metabolism, HIV drug metabolism and pharmacogenetics.3) However, there had been no study on pharmacokinetic interaction between alcohol and HIV drugs.In our previous reports, 4,5) we recognized that bioavailability of saquinavir (SQV), a potent protease inhibitor, after oral administration was retarded during alcohol consumption both in HIV-infected patients and ethanol-treated rats. The bioavailability of SQV after oral administration alone to rats treated with 15% ethanol solution for 14 d (Day 14 rats) decreased significantly by 51% as compared to non treated (NT) rats. 5) Moreover, total body clearance of SQV after intravenous administration alone to the Day 14 rats increased slightly by 30% as compared to the NT rats. 5) Although most alcoholic beverages contain 0.13 to 0.5% isopentanols that inhibit CYP3A, 6) it has been well known that the greater part of constituent of alcohol beverages, ethanol, induces mainly CYP2E1. Since SQV is one of PIs to be used for HAART therapy and is mainly metabolized via CYP3A4, 7) a room to clarify the reason that ethanol decreases the bioavailability of SQV after oral administration has been remained. In this study, to solve this contradiction that we observed in both clinical practice and ethanol-treated rats, the factors to decrease the bioavailability of SQV during ethanol consumption were evaluated. Where, we focused on the metabolism of SQV via CYP enzymes, the efflux pump; P-glycoprotein (Pgp) and the phase II metabolism in ethanol-treated rats. MATERIALS AND METHODSChemicals SQV was kindly supplied by HoffmanLaRoche Inc. (Nutley, NJ, U.S.A.). Rhodamine 123 (Rho123), ketoconazole (KCZ), cyclosporin A (CsA), Glucose-6-phosphate (G6P), G6P dehydrogenase (G6PDH) and nicotineamide adenosine dinucleotide phosphate (NADP) were obtained from Sigma Chemicals (St. Louis, MO, U.S.A.). Testosterone, 1-naphtol, 4-methylumbelliferone (4-MU) and 1-chloro-2,4-dinitrobenzene (CDNB) were purchased from Nacalai tesque (Kyoto, Japan). Ethanol and all other reagents used were of analytical grade and were used without further purification.Preparation of Ethanol-Treated Rats Male Wistar rats of about 8-9 weeks ol...