title: In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp.
abstract: The bioavailability, fraction of dose that reaches systemic circulation, of orally administered drugs is often limited by both physical barriers of the intestine (e.g., unstirred-water and mucosal layers, epithelial tight junctions) as well as biochemical barriers such as cytochromes P450 (CYP) and P-glycoprotein (P-gp). Highly expressed in intestine and liver, CYP and P-gp can limit the systemic-availability of parent-drug by metabolism and efflux, respectively, by means of similarly large and flexible active sites that accommodate a variety of structurally-diverse, lipophilic molecules over a wide-range of molecular weights. Consequently, many molecules that are substrates for CYP3A4 also demonstrate affinity for P-gp and numerous studies have reported that for these dual-substrates, CYP3A4 and P-gp afford an interplay that affects bioavailability and clearance in a manner that is non-linear. Several in vitro and in situ models of metabolism and permeability, including transfected cell lines, isolated tissues and perfused organs as well as computational models including physiologically-based pharmacokinetic models of such co-expressing systems have demonstrated this phenomenon of CYP3A/Pgp interplay. Furthermore, recent availability of ligand bound X-ray co-crystal structures of the CYP3A4 and P-gp binding sites coupled with computational docking techniques and other validated in silico models, provide medicinal chemists with tools to inform structural-design modifications that can modify the interaction with one or both proteins. This article provides a review of relevant in silico, in vitro, ex vivo and in situ models that allow for investigation of the extent to which clearance or bioavailability can be affected by CYP/P-gp interplay.
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. Mudra_Daniel_Robert@lilly.com
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Desino
authors.forename: Prashant V
authors.initials: PV
authors.lastname: Desai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D011487:Protein Conformation; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A