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Vol. 56, Issue 2, 383-389, August 1999
Divisions of Gastroenterology and Clinical Pharmacology,
Departments of Internal Medicine and Research, University Clinic
(Kantonsspital and Children's Hospital), Basel, Switzerland
(H.G., J.D., M.T.); Institute for Pharmaceutical Technology and
Biopharmacy, University of Heidelberg, Heidelberg, Germany (G.F.);
Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, North Carolina (D.S.M.); and Mount Desert Island
Biological Laboratory, Salsbury Cove, Maine (H.G., G.F., D.S.M.)
We used renal proximal tubules from a teleost fish (killifish;
Fundulus heteroclitus), fluorescent substrates and
confocal microscopy to study the interactions between human
immunodeficiency virus protease inhibitors and drug-transporting
ATPases. Both saquinavir and ritonavir inhibited luminal accumulation
of a fluorescent cyclosporin A derivative (a substrate for
P-glycoprotein) and of fluorescein methotrexate [a substrate for
multidrug resistance-associated protein 2 (Mrp2)]. Of the two protease
inhibitors, ritonavir was the more potent inhibitor of transport by a
factor of at least 20. Ritonavir was at least as good an inhibitor of
P-glycoprotein- and Mrp2-mediated transport as cyclosporin A and
leukotriene C4, respectively. Inhibition of P-glycoprotein- and
Mrp2-mediated transport was not due to toxicity or impaired metabolism,
because neither saquinavir nor ritonavir inhibited transport of
fluorescein on the renal organic anion system. Experiments with a
fluorescent saquinavir derivative showed strong secretion into the
tubular lumen that was inhibited by verapamil, leukotriene C4,
saquinavir, and ritonavir. Together, the data demonstrate that
saquinavir, and especially ritonavir, are potent inhibitors of
P-glycoprotein- and Mrp2-mediated transport. The experiments with the
fluorescent saquinavir derivative suggest that these protease
inhibitors may also be substrates for both P-glycoprotein and Mrp2.
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