title: Clarification of P-glycoprotein inhibition-related drug-drug interaction risks based on a literature search of the clinical information.
abstract: 1. Recently, the Food and Drug Administration (FDA) and European Medicines Agency have shown decision trees to determine whether a drug candidate is an inhibitor of P-glycoprotein (P-gp). However, there has been no clear information on whether P-gp inhibition can be significant in clinical drug-drug interactions (DDIs). The purpose of this study was to confirm the effect of P-gp inhibition through comprehensive analysis of the clinical DDI studies. 2. Clinical information on P-gp inhibition was collected using the University of Washington Metabolism and Transport Drug Interaction Database™. The risks of P-gp inhibition-related DDI were qualitatively evaluated in terms of the contribution of CYP3A inhibition. The degrees of DDI risk were categorized using the area under the plasma concentration-time curve increase ratio (AUCR), according to the FDA DDI criteria. 3. When both P-gp and CYP3A were inhibited, the DDI risks were potent in 25% of the studies. When CYP3A inhibition did not contribute to the DDI, no study was categorized as potent DDI risk, and the detailed analysis revealed that AUCRs were basically <3.0. The DDI risk caused by P-gp inhibition solely would be limited, although the use of P-gp substrates with narrow therapeutic range should be carefully controlled.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Umeyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Teruaki
authors.initials: T
authors.lastname: Okuda
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D019540:Area Under Curve; D001692:Biological Transport; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D016208:Databases, Factual; D004347:Drug Interactions; D006801:Humans; D018570:Risk Assessment
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A
keywords: CYP3A; P-glycoprotein; drug–drug interaction