title: Predicting drug-drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein.
abstract: Recently, interest has grown in drug-drug interactions (DDIs) involving the inhibition of intestinal CYP3A4, P-glycoprotein (P-gp), and other drug efflux transporters. The criteria for intestinal DDIs are described in the draft guidances of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Substrate drugs with small fraction absorbed (Fa) and/or low intestinal availability (Fg) as a result of intestinal efflux transport and metabolism are important as "victim" drugs because these substrates are likely to show considerable interactions. The susceptibility of a victim drug to intestinal interactions can be evaluated from its FaFg. In this review, methods for estimating the FaFg of substrate drugs are discussed. The nonlinear pharmacokinetics of substrate drugs caused by the saturation of intestinal CYP3A4/P-gp is also discussed. The methods for predicting intestinal DDIs caused by inhibitor drugs are then summarized. Because the prediction accuracy of intestinal DDIs also depends on the inhibition constant (Ki) estimated in in vitro studies, these in vitro methods of estimating Ki are also discussed. Standardized methods for predicting intestinal DDIs have not yet been established. Further studies are required to establish more accurate and standardized prediction methods.
authors.affiliation: Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Junichi
authors.initials: J
authors.lastname: Takano
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D010599:Pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A