Evaluation of factors to decrease plasma concentration of an HIV protease inhibitor, saquinavir in ethanol-treated...

Area of Science:

• Pharmacology
• Drug Metabolism
• Toxicology

Background:

• Alcohol consumption is known to affect drug bioavailability, but the mechanisms for saquinavir (SQV) are unclear.
• Understanding these interactions is crucial for optimizing antiretroviral therapy.

Purpose of the Study:

• To investigate the factors contributing to decreased plasma concentration of saquinavir (SQV) in ethanol-treated rats.
• To elucidate the role of intestinal efflux and metabolism in reduced SQV oral bioavailability.

Main Methods:

• Ethanol-treated rats (15% solution for 14 days) were used to assess SQV pharmacokinetics.
• Exsorption and biliary excretion clearance of SQV were measured.
• Intestinal and liver microsomes were analyzed for metabolic clearance rates (V(max)/K(m)).
• Inhibition studies with ketoconazole (KCZ) and cyclosporin A (CsA) were performed.

Main Results:

• Ethanol-treated rats showed a 6-fold increase in SQV exsorption clearance from blood to the jejunum.
• Biliary excretion clearance of SQV increased by 1.8-fold in ethanol-treated rats.
• Metabolic clearance rate of SQV increased in intestinal microsomes but not liver microsomes.
• Ketoconazole and cyclosporin A significantly increased portal vein SQV plasma concentration, with CsA showing a superior effect.

Conclusions:

• Reduced SQV oral bioavailability in ethanol consumers is likely due to enhanced intestinal and hepatic efflux.
• Ethanol consumption may lead to functional enhancement or overexpression of P-glycoprotein.
• Phase II metabolism activation is unlikely to be the primary cause of reduced SQV bioavailability.