title: Individual and combined roles of CYP3A, P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) in the pharmacokinetics of docetaxel.
abstract: Docetaxel is one of the most widely used anticancer drugs. A major problem with docetaxel treatment, however, is the considerable interpatient variability in docetaxel exposure. Another disadvantage of the drug is that it has a very low oral bioavailability and can, therefore, only be administered intravenously. The drug-metabolizing enzyme CYP3A and the drug transporter MDR1 (P-glycoprotein) are major determinants of docetaxel pharmacokinetics. In vitro studies have indicated that docetaxel is also a substrate for the drug transporter MRP2, but the in vivo importance of MRP2 for docetaxel is currently unknown. We, therefore, investigated the role of MRP2 in the pharmacokinetics of docetaxel by utilizing Mrp2(-/-) mice. We also generated and characterized Cyp3a/Mdr1a/b/Mrp2(-/-) combination knockout mice to get more insight into how these drug-handling systems work together in determining docetaxel pharmacokinetics. The systemic exposure in Mrp2(-/-) mice was not significantly different from wild-type, after either oral or intravenous administration. Strikingly, however, in Cyp3a/Mdr1a/b/Mrp2(-/-) mice, systemic docetaxel exposure was increased 166-fold after oral administration when compared with wild-type mice, and 2.3-fold when compared with Cyp3a/Mdr1a/b(-/-) mice. Interestingly, this 166-fold increase was disproportionate compared with that for the separate Cyp3a (12-fold) or Mdr1a/b/Mrp2 (4-fold) knockouts. The oral bioavailability was increased to 73% in the Cyp3a/Mdr1a/b/Mrp2(-/-) strain, versus only 10% in wild-type mice. Our data thus indicate that in the absence of CYP3A and Mdr1a/b activity, Mrp2 has a marked impact on docetaxel pharmacokinetics. These findings could have important implications for improving the oral bioavailability and reducing the variability in docetaxel exposure.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Robert A B
authors.initials: RA
authors.lastname: van Waterschoot
authors.forename: Jurjen S
authors.initials: JS
authors.lastname: Lagas
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D000077143:Docetaxel; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D043823:Taxoids / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D008565:Membrane Proteins
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000077143:Docetaxel; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D043823:Taxoids; C507084:Abcb1b protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins