P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs.

Orally administered anti-HIV drugs must be adequately and consistently absorbed for therapy to be successful. This review discusses the barriers to achieving oral bioavailability for the currently available anti-HIV drugs. Most reverse transcriptase inhibitors have good oral bioavailabilities. Didanosine bioavailability could be reduced by acid instability, first-pass hepatic metabolism, and possibly poor intestinal permeation. Bioavailability of zidovudine is also reduced by first-pass metabolism. The non-nucleoside reverse transcriptase inhibitors have oral bioavailabilities most probably limited by poor aqueous solubility. For each of the currently marketed HIV protease inhibitors, solubility, intestinal permeability, and first-pass metabolism could contribute to reducing oral bioavailability. The intestinal permeabilities of these agents is influenced by secretory transport. In vitro, secretory transport, which appears to be P-glycoprotein-mediated, is much greater than permeation in the absorptive direction for indinavir, nelfinavir, ritonavir, and saquinavir. The mechanisms of secretory intestinal transport are reviewed, and the factors that may influence the impact of secretory transport in vivo are considered.