Maeda2014

Introduction to Organic Anion Transporters (OATs)

  • Inhibitory effects of p-aminohippurate (PAH) and probenecid on renal clearance of adefovir and benzylpenicillin as probe drugs for OAT1 and OAT3.

  • Background study conducted by Kazuya Maeda et al. at various institutions in Japan.

  • Specific aim: To evaluate the in vivo functions of renal OATs using probe drugs and inhibitors.

Study Overview

  • Probe Drugs:

    • Adefovir: Selected for OAT1.

    • Benzylpenicillin: Selected for OAT3.

  • Inhibitors:

    • Probenecid: Potent inhibitor of both OAT1 and OAT3.

    • PAH: Selective for OAT1, assists in evaluating renal excretion processes.

In Vitro Inhibition Studies

  • Renal clearance studies involved human kidney slices.

  • Findings indicated:

    • Probenecid inhibited adefovir and benzylpenicillin uptake with Ki values of 18.6 ± 5.1 µM and 12.6 ± 4.2 µM, respectively.

    • PAH primarily inhibited adefovir uptake, demonstrating its selectivity for OAT1.

Clinical Drug-Interaction Study

  • Design: Crossover study with healthy subjects; drugs administered together with different doses of probenecid and PAH.

  • Key results:

    • Adefovir clearance reduced by 45% (probenecid) and 46% (PAH).

    • Benzylpenicillin clearance reduced by 78% (maximum probenecid dose), but unexpectedly increased by 47% with PAH infusion.

Mechanisms of Action and Implications

  • Importance of OATs in drug metabolism and interaction:

    • OAT1 and OAT3 mediate tubular secretion affecting pharmacokinetics of drugs.

    • Inhibitory effects of PAH and probenecid provide insights into drug-drug interactions (DDIs).

  • Relevance of findings:

    • The outcome of the study provides a framework for assessing the clinical significance of DDIs in drug development processes.

Conclusions

  • Adefovir and benzylpenicillin validated as probe drugs for studying OAT1 and OAT3 activity in humans.

  • Probenecid and PAH serve as useful tools to investigate transporter-mediated excretion and elucidate DDI risks.

  • Results relevant for designing future clinical studies examining renal transporter interactions.

References

  • A comprehensive list of studies discussing the characteristics and relevance of OATs in pharmacology, including guidelines provided by EMA and FDA for assessing drug interactions.