P-Glycoprotein Limits Oral Availability, Brain, and Fetal Penetration of Saquinavir Even with High Doses of Ritonavir

• Published in: Molecular pharmacology Vol. 59; no. 4; pp. 806 - 813
• Main Authors: Huisman, Maarten T., Smit, Johan W., Wiltshire, Hugh R., Hoetelmans, Richard M.W., Beijnen, Jos. H., Schinkel, Alfred H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2001; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Administration, Oral; Animals; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological Availability; Blood-Brain Barrier - drug effects; Brain - drug effects; Brain - metabolism; Cell Line; Dose-Response Relationship, Drug; Drug Synergism; Female; Fetus - drug effects; Fetus - metabolism; Humans; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; Liver - drug effects; Liver - metabolism; LLC-PK1 Cells; Maternal-Fetal Exchange - drug effects; Mice; Mice, Knockout; Pregnancy; Ritonavir - administration & dosage; Saquinavir - administration & dosage; Saquinavir - pharmacokinetics; Swine; Transfection; HPI; P-gp; Mdr1a/1b; HPLC; HAART; AUC
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1016/S0026-895X(24)09249-6

The low oral bioavailability of the HIV protease inhibitor (HPI) saquinavir is dramatically increased by coadministration of the HPI ritonavir. Because saquinavir and ritonavir are substrates and inhibitors of both the drug transporter P-glycoprotein (P-gp) and of the metabolizing enzyme CYP3A4, we wanted to sort out whether the ritonavir effect is primarily mediated by inhibition of CYP3A4 or P-gp or both. P-gp is known to limit the bioavailability, brain, testis, and fetal penetration of its substrates, so effective inhibition of P-gp by ritonavir in vivo might open up pharmacological sanctuary sites for saquinavir, with the potential of beneficial effects on therapy, but also of increased toxicity. In vitro, P-gp-mediated transport of saquinavir and ritonavir was only moderately inhibited by both HPIs compared with the potent P-gp inhibitor PSC833. When [14C]saquinavir was orally coadministered with a maximum tolerated dose of ritonavir to wild-type and P-gp-deficient mice, saquinavir bioavailability was dramatically increased in both strains, but P-gp still limited the oral bioavailability of saquinavir, and its penetration into brain and fetus. These data indicate that in vivo, ritonavir is a relatively poor P-gp inhibitor. The highly increased bioavailability of saquinavir because of ritonavir coadministration most likely results from reduced saquinavir metabolism. Importantly, our data indicate that it is unlikely that ritonavir coadministration will substantially affect the contribution of P-gp to pharmacological sanctuary sites such as brain, testis, and fetus. Thus, if one wanted to effectively open these sites for therapeutic purposes, more efficient P-gp inhibitors should be applied.