title: Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport.
abstract: Tebipenem pivoxil (TBPM-PI) is an oral carbapenem antibiotic for treating otolaryngologic and respiratory infections in pediatric patients. This agent is a prodrug to improve intestinal absorption of TBPM, an active form, and an absorption rate of TBPM-PI is higher than those of other prodrug-type β-lactam antibiotics. In the present study, we hypothesized that a certain mechanism other than simple diffusion is involved in the process of improved intestinal absorption of TBPM-PI and examined the mechanism. TBPM-PI uptake by Caco-2 cells was decreased by ATP-depletion and lowering the temperature to 4 °C, suggesting the contribution of carrier-mediated transport mechanisms. This uptake was partially decreased by ACE inhibitors, and the reduction of the absorption by captopril was observed by in vivo study and in situ single-pass intestinal perfusion study in rat, supporting the contribution of influx transporters. Since some ACE inhibitors and β-lactam antibiotics are reported to be substrates of PEPT and OATP families, we measured transporting activity of TBPM-PI by intestinally expressed transporters, PEPT1, OATP1A2, and OATP2B1. As a result, significant transport activities were observed by both OATP1A2 and OATP2B1 but not by PEPT1. Interestingly, pH dependence of TBPM-PI transports was different between OATP1A2 and OATP2B1, showing highest activity by OATP1A2 at pH 6.5, while OATP2B1-mediated uptake was higher at neutral and weak alkaline pH. OATP1A2 exhibited higher affinity for TBPM-PI (K(m) = 41.1 μM) than OATP2B1 (K(m) > 1 mM) for this agent. These results suggested that TBPM-PI has high intestinal apical membrane permeability due to plural intestinal transport routes, including the uptake transporters such as OATP1A2 and OATP2B1 as well as simple diffusion.
authors.affiliation: Applied Pharmacology Research Laboratories, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kato
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Erika
authors.initials: E
authors.lastname: Kuraoka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Maki
authors.initials: M
authors.lastname: Iguchi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Tohru
authors.initials: T
authors.lastname: Kurosawa
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002216:Captopril / Q000494:pharmacology; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D000074011:Peptide Transporter 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism; D014981:Xenopus
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D027361:Organic Anion Transporters; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; C512988:SLCO1A2 protein, human; C450859:SLCO2B1 protein, human; D027981:Symporters; D002216:Captopril; C500135:tebipenem