Changes of drug pharmacokinetics mediated by downregulation of kidney organic cation transporters Mate1 and Oct2 in a rat model of hyperuricemia

PLoS One. 2019 Apr 5;14(4):e0214862. doi: 10.1371/journal.pone.0214862. eCollection 2019.

Abstract

The effects of hyperuricemia on the expression of kidney drug transporters and on the pharmacokinetics of several substrate drugs were examined. We first established a rat model of hyperuricemia without marked symptoms of chronic kidney failure by 10-day co-administration of oxonic acid (uricase inhibitor) and adenine (biosynthetic precursor of uric acid). These hyperuricemic rats showed plasma uric acid concentrations of up to 6 mg/dL, which is similar to the serum uric acid level in hyperuricemic humans, with little change of inulin clearance. The mRNA levels of multidrug and toxin extrusion 1 (Mate1, Slc47a1), organic anion transporter 1 (Oat1, Slc22a6), organic cation transporter 2 (Oct2, Slc22a2), urate transporter 1 (Urat1, Slc22a12) and peptide transporter 1 (Pept1, Slc15a1) were significantly decreased in kidney of hyperuricemic rats. Since Oct2, Mate1 and Oat1 are important for renal drug elimination, we next investigated whether the pharmacokinetics of their substrates, metformin, cephalexin and creatinine, were altered. The plasma concentration of metformin was not affected, while its kidney tissue accumulation was significantly increased. The plasma concentration and kidney tissue accumulation of cephalexin and the plasma concentration of creatinine were also increased. Furthermore, the protein expression of kidney Mate1 was decreased in hyperuricemic rats. Accordingly, although multiple factors may influence renal handling of these drugs, these observations can be accounted for, at least in part, by downregulation of Mate1-mediated apical efflux from tubular cells and Oct2-mediated basolateral uptake. Our results suggest that hyperuricemia could alter the disposition of drugs that are substrates of Mate1 and/or Oct2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / administration & dosage
  • Animals
  • Antiporters / genetics*
  • Antiporters / metabolism*
  • Cephalexin / blood
  • Cephalexin / pharmacokinetics
  • Creatinine / blood
  • Creatinine / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Humans
  • Hyperuricemia / blood
  • Hyperuricemia / genetics*
  • Hyperuricemia / metabolism*
  • Kidney / drug effects
  • Kidney / metabolism*
  • Male
  • Metformin / blood
  • Metformin / pharmacokinetics
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism*
  • Organic Cation Transporter 2 / genetics*
  • Organic Cation Transporter 2 / metabolism*
  • Oxonic Acid / administration & dosage
  • Pharmacokinetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Uric Acid / administration & dosage

Substances

  • Antiporters
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • RNA, Messenger
  • Slc22a2 protein, rat
  • Slc47a1 protein, rat
  • Uric Acid
  • Oxonic Acid
  • Metformin
  • Creatinine
  • Adenine
  • Cephalexin

Grant support

This work was supported by Grant-in-Aid for Challenging Exploratory Research (KAKENHI, 16K15158) to Ikumi Tamai from the Japan Society for the Promotion of Science. Noriaki Yoda is an employee of Otsuka Pharmaceutical Co., Ltd., and received salary. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.