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: Kazuhiko Kato, Yoshiyuki Shirasaka, Erika Kuraoka, Akihiro Kikuchi, Maki Iguchi, Hisashi Suzuki, Shigeki Shibasaki, Tohru Kurosawa, Ikumi Tamai
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 7 Issue 5 Pg. 1747-56 (Oct 04 2010) ISSN: 1543-8392 [Electronic] United States
• PMID: 20735088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Carbapenems
• Organic Anion Transporters
• Peptide Transporter 1
• SLC15A1 protein, human
• SLCO1A2 protein, human
• SLCO2B1 protein, human
• Symporters
• Captopril
• tebipenem

Topics

• Administration, Oral
• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics)
• Biological Transport, Active
• Caco-2 Cells
• Captopril (pharmacology)
• Carbapenems (administration & dosage, pharmacokinetics)
• Female
• Humans
• Hydrogen-Ion Concentration
• Intestinal Absorption (drug effects, physiology)
• Kinetics
• Male
• Oocytes (metabolism)
• Organic Anion Transporters (metabolism)
• Peptide Transporter 1
• Rats
• Rats, Sprague-Dawley
• Symporters (metabolism)
• Xenopus