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 abso rbed for therapy to be successful. This review discusses the barriers to ac hieving oral bioavailability for the currently available anti-MN drugs. Mos t reverse transcriptase inhibitors have good oral bioavailabilities, Didano sine bioavailability could be reduced by acid instability, first-pass hepat ic metabolism and possibly poor intestinal permeation. Bioavailability of z idovudine is also reduced by first-pass metabolism. The non-nucleoside reve rse transcriptase inhibitors have oral bioavailabilities most probably limi ted by poor aqueous solubility, For each of the currently marketed HIV prot ease inhibitors, solubility, intestinal permeability, and first-pass metabo lism could contribute to reducing oral bioavailability. The intestinal perm eabilities of these agents is influenced by secretory transport. In vitro, secretory transport, which appears to be P-glycoprotein-mediated, is much g reater than permeation in the absorptive direction for indinavir, nelfinavi r, ritonavir, and saquinavir. The mechanisms of secretory intestinal transp ort are reviewed, and the factors that may influence the impact of secretor y transport in vivo are considered. (C) 1999 Elsevier Science B.V. All righ ts reserved.