Important note: Information in this article was accurate in May 2001. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, May 21, 2001
Michael Greer, Staff Medical Writer
NewsRx - Combining ritonavir with saquinavir does not give the HIV drugs access to areas blocked by P-glycoprotein (P-gp), researchers in the Netherlands say.
"The low oral bioavailability of the HIV protease inhibitor (HPI) saquinavir is dramatically increased by co-administration of the HPI ritonavir," M.T. Huisman and colleagues explained in the journal Molecular Pharmacology. "P-gp is known to limit the ... 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 the drugs.
However, Huisman and coworkers found that ritonavir's effects are not mediated by P-gp inhibition and will not provide entry to such sanctuary sites.
Compared with PSC833, a substance known to potently inhibit P-gp activity, ritonavir had little effect on P-gp-mediated saquinavir transport. Access to sanctuary sites was blocked by P-gp even in mice genetically deficient in the drug transporter, study data showed.
Huisman and colleagues suggested that ritonavir increases saquinavir bioavailability by inhibiting the enzyme CYP3A4 instead. Blocking the activity of this enzyme would curtail saquinavir metabolism, they noted.
The P-gp barrier may not be entirely negative, as it does protect sensitive regions, such as the brain and testes, from protease inhibitor toxicity ("P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir," Mol Pharmacol 2001 Apr;59(4):806-13.
Huisman and colleagues concluded that their "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."
The corresponding author for this report is A.H. Schinkel, Netherlands Cancer Institute, Division of Experimental Therapy, Plesmanlaan 121, NL-1066 CX Amsterdam, the Netherlands.
A search at www.NewsRx.net using the term "AIDS and HIV therapy" yielded 1,191 articles in six specialized reports.
Key points reported in this study include:
This article was prepared by AIDS Weekly editors from staff and other reports.
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