title: Cytochrome p450 inhibitory properties of common efflux transporter inhibitors.
abstract: Drug transporter inhibitors are important tools to elucidate the contribution of transporters to drug disposition both in vitro and in vivo. These inhibitors are often unselective and affect several transporters as well as drug metabolizing enzymes, which can make experimental results difficult to interpret with confidence. We therefore tested 14 commonly used P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug-resistance associated protein (MRP) inhibitors as inhibitors of cytochrome P450 (P450) enzyme activities using recombinant enzymes. A subset of P-gp and/or CYP3A inhibitors were selected (cyclosporin A, elacridar, ketoconazole, quinidine, reserpine, and tacrolimus) for a comparison of P450 inhibition in human microsomes and hepatocytes. Most P-gp inhibitors showed CYP3A4 inhibition, with potencies often in a similar range as their P-gp inhibition, as well as less potent CYP2C19 inhibition. Other P450 enzymes were not strongly inhibited except a few cases of CYP2D6 inhibition. MRP and BCRP inhibitors showed limited P450 inhibition. Some inhibitors showed less P450 inhibition in human hepatocytes than human liver microsomes, for example, elacridar, probably due to differences in binding, permeability limitations, or active, P-gp mediated efflux of the inhibitor from the hepatocytes. Quinidine was a potent P450 inhibitor in hepatocytes but only showed weak inhibition in microsomes. Quinidine shows an extensive cellular uptake, which may potentiate intracellular P450 inhibition. Elacridar, described as a potent and selective P-gp inhibitor, displayed modest P450 inhibition in this study and is thus a useful model inhibitor to define the role of P-gp in drug disposition without interference with other processes.
authors.affiliation: CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Englund
authors.forename: Patrik
authors.initials: P
authors.lastname: Lundquist
authors.forename: Cristine
authors.initials: C
authors.lastname: Skogastierna
authors.forename: Jenny
authors.initials: J
authors.lastname: Johansson
authors.forename: Janet
authors.initials: J
authors.lastname: Hoogstraate
authors.forename: Lovisa
authors.initials: L
authors.lastname: Afzelius
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
authors.forename: Denis
authors.initials: D
authors.lastname: Projean
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D015925:Cryopreservation; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D065607:Cytochrome P-450 Enzyme Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations; C116614:ABCG2 protein, human