Oral absorption of the HIV protease inhibitors: a current update

Although the human immunodeficiency virus (HIV) protease inhibitors are hig hly effective, they are characterized by low and/or variable bioavailabilit y with Limited penetration into the central nervous system (CNS). Their cli nical use is limited by patient compliance and by drug-drug interactions. T he effect of drug solubility on their oral absorption has been investigated but further evaluation of this relationship is required. First pass metabo lism appears to be significant for the HIV protease inhibitors and they are extensively metabolized by cytochrome P450 (CYP) 3A4. Recent studies sugge st that these drugs are substrates for the P-glycoprotein efflux pump; whic h can limit their intestinal absorption and their transport across the bloo d-brain barrier. Drugs inducing or inhibiting CYP3A4 and/or P-glycoprotein may influence the bioavailability of the HIV protease inhibitors. The low b ioavailability, variable absorption and drug-drug interactions of the HIV p rotease inhibitors may be related to the variability of cytochrome P450 and P-glycoprotein expression and to possible CYP3A4/P-glycoprotein interactio ns. To improve oral HN protease inhibitor therapy, it is essential to mecha nistically characterize the cell specific, tissue specific and regional int estinal dependencies of drug transport, secretory transport, metabolism and P-glycoprotein/CPY3A4 interactions. This report reviews the physicochemica l characteristics and pharmacokinetics of the HIV protease inhibitors while considering the relationships between their hepatic and intestinal metabol ism, low bioavailability, variable absorption and drug-drug interactions. ( C) 1999 Elsevier Science B.V. All rights reserved.