title: Variability of bioavailability and intestinal absorption mechanisms of metoprolol.
abstract: We previously reported that aging and/or cytochrome P450 2D6 polymorphism are responsible for the interindividual variability in the systemic clearance (CL) and bioavailability (F) of metoprolol. The aim of the present study was to evaluate the residual variability of F of metoprolol in routinely treated Japanese patients and to investigate the intestinal absorption mechanism of the drug using human intestinal epithelial LS180 cells. We first re-analyzed the blood concentration data for metoprolol in 34 Japanese patients using a nonlinear mixed effects model. The oral clearance (CL/F) of metoprolol was positively correlated with the apparent volume of distribution (V/F), suggesting the residual variability of F. The uptake of metoprolol into LS180 cells was significantly decreased by the acidification of extracellular medium pH, and was dependent on temperature and intracellular pH. Furthermore, the cellular uptake of metoprolol was saturable, and was significantly decreased in the presence of hydrophobic cationic drugs such as diphenhydramine, procainamide, bisoprolol, and quinidine. These findings indicate that residual variability of F is one of the causes of the interindividual pharmacokinetic variability of metoprolol, and that the interindividual variability of not only presystemic first-pass metabolism, but also intestinal absorption, may be responsible for the variable F of the drug.
authors.affiliation: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama.
authors.forename: Miki
authors.initials: M
authors.lastname: Fukao
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.forename: Asuka
authors.initials: A
authors.lastname: Horie
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000284:Administration, Oral; D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000368:Aged; D044466:Asian People; D001682:Biological Availability; D002460:Cell Line; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007564:Japan; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D013696:Temperature
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D008790:Metoprolol