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Vol. 59, Issue 4, 806-813, April 2001
Division of Experimental Therapy, The Netherlands Cancer Institute,
Amsterdam, The Netherlands (M.T.H., J.W.S., A.H.S.); Drug Development,
F. Hoffmann-La Roche, Welwyn Garden City, United Kingdom (H.R.W.); and
Department of Pharmacy and Pharmacology, Slotervaart Hospital,
Amsterdam, The Netherlands (R.M.W.H., J.H.B.)
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.
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