Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats

Abstract

Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78+/-0.10 to 0.38+/-0.03 microg h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30+/-0.06 to 0.57+/-0.05 microg h/ml and from 17.63+/-1.66 to 4.18+/-0.94 microg h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake.

Alcohol consumption effect on antiretroviral therapy and HIV-1 pathogenesis: role of cytochrome P450 isozymes

“…Nonetheless, this is an important finding in context with the report that alcohol is known to increase the toxicity and reduce the efficacy of HAART in HIV-1-infected individuals [26,28,86-88]. More specifically, the studies from Flexner and colleagues [88] and Shibata and colleagues [89,90] have shown that alcohol can increase the metabolism and decrease the bioavailability of PI and NNRTI, resulting in decreased efficacy. The presence of multiple PI and/or NNRTI in HAART regimen, in which PI also act as CYP3A4 inhibitors, make alcohol–CYP3A4–PI interactions complex.…”

Evaluation of Factors to Decrease Plasma Concentration of an HIV Protease Inhibitor, Saquinavir in 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.…”

“…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 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.…”

A Pharmacokinetic Model for Evaluating the Impact of Hepatic and Intestinal First-Pass Loss of Saquinavir in the Rat

“…After intravenous administration, samples were collected at 8 to 10 h, which was considered to represent the terminal phase, because previous studies have estimated the half-life (t 1/2 ) of SQV to be 1.6 h in rats (Shibata et al, 2003). However, after intraperitoneal and oral administration, profiles showed that the initial protocol sampling times (up to 8 -10 h) had not adequately captured the terminal phase and were therefore modified.…”