Intestinal Absorption Mechanism of Tebipenem Pivoxil, a Novel Oral Carbapenem: Involvement of Human OATP Family in Apical Membrane Transport
| Autor: | Ikumi Tamai, Kazuhiko Kato, Erika Kuraoka, Hisashi Suzuki, Akihiro Kikuchi, Shigeki Shibasaki, Yoshiyuki Shirasaka, Maki Iguchi, Tohru Kurosawa |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Captopril medicine.drug_class Xenopus Tebipenem Antibiotics Administration Oral Biological Transport Active Organic Anion Transporters Pharmaceutical Science Absorption (skin) Pharmacology Peptide Transporter 1 Intestinal absorption Rats Sprague-Dawley chemistry.chemical_compound In vivo Drug Discovery medicine Animals Humans Symporters Chemistry Hydrogen-Ion Concentration Prodrug Apical membrane Anti-Bacterial Agents Rats Kinetics Carbapenems Intestinal Absorption Oocytes Molecular Medicine Female Caco-2 Cells medicine.drug |
| Zdroj: | Molecular Pharmaceutics. 7:1747-1756 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp100130b |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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