title: Prediction of nonlinear intestinal absorption of CYP3A4 and P-glycoprotein substrates from their in vitro Km values.
abstract: OBJECTIVE
  CYP3A4 and P-glycoprotein (P-gp) are present in the human intestine and mediate intestinal first-pass metabolism and the efflux of oral drugs, respectively. We aimed to predict whether intestinal CYP3A4/P-gp is saturated in a therapeutic dose range.
  
  
  METHODS
  Information on the Michaelis-Menten constant (Km), product of the fraction absorbed (Fa) and intestinal availability (Fg) (FaFg) of CYP3A4/P-gp substrates, and clinical AUC data including two or more different dosages for each CYP3A4/P-gp substrate was collected. The relationship between dose-normalized AUC and dose/Km value, termed the linearity index (LIN), was analyzed.
  
  
  RESULTS
  Among 38 CYP3A4 and/or P-gp substrates, 16 substrates exhibited nonlinear pharmacokinetics and 22 substrates exhibited linear pharmacokinetics. Substrates with a small LIN tended to exhibit linear pharmacokinetics. The smallest LIN values of a substrate that exhibited nonlinear pharmacokinetics were 2.8 and 0.77 L for CYP3A4 and P-gp substrates, respectively. A decision tree for predicting nonlinear pharmacokinetics of CYP3A4/P-gp substrates based on LIN and FaFg of drugs was proposed. This decision tree correctly predicted linearity or nonlinearity for 24 of 29 drugs.
  
  
  CONCLUSIONS
  LIN is useful for predicting CYP3A4/P-gp-mediated nonlinearity in intestinal absorption process in humans.
authors.affiliation: Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan. tachibanatth@chugai-pharm.co.jp
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003663:Decision Trees; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A