. The long term objective of the proposed research is to provide a rational and mechanistic basis for improving oral drug absorption in the treatment of AIDS and AIDS-related opportunistic infections. Previous research from this group has demonstrated that many anti-AIDS drugs utilize numerous intestinal carrier-mediated absorptive and secretory transport mechanisms. For many new anti-AIDS drugs or new drugs for opportunistic infections in AIDS patients, the cellular and molecular mechanisms whereby these agents interact with or pass across the epithelial barrier of the intestine remains largely unknown. The specific drugs to be studied include HIV protease inhibitors (saquinavir, ritonavir), non-nucleoside reverse transcriptase inhibitors (delaviridine, UC-781), and antiherpetic/anti-CMV agents (valacyclovir, lobucavir). These drugs have been chosen for study because they are clinically significant agents, have been reported to be involved in significant drug interactions, have low to moderate oral bioavailability, and they demonstrate significant variability in bioavailability due to mechanisms other than hepatic metabolism. To address the pharmacokinetic problems associated with these agents, the following specific aims are proposed: 1) To determine the mechanisms and regional dependence of intestinal/hepatic metabolism and transport across the intestinal mucosa, 2) To investigate the regulation of absorptive and secretory flux and its effect on the variability of drug permeability and bioavailability, and 3) To integrate the mechanism-based, in vitro intestinal transport and metabolism parameters with macroscopic gastrointestinal and systemic disposition parameters to estimate oral drug bioavailability and variability.