Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8)

Sook Wah Yee, Anh Nguyet Nguyen, Chaline Brown, Radojka M. Savic, Youcai Zhang, Richard A. Castro, Cheryl D. Cropp, Ji Ha Choi, Diment Singh, Harunobu Tahara, Sophie L. Stocker, Yong Huang, Claire M. Brett, Kathleen M. Giacomini

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293-Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, Vmax, [159 ± 3 nmol*(mg protein)-1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)-1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values (Km) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CLR; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CLsec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CLR and CLsec.

Original languageEnglish
Pages (from-to)3451-3457
Number of pages7
JournalJournal of Pharmaceutical Sciences
Volume102
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • Cefotaxime
  • OAT3
  • Organic anion transporter
  • Pharmacogenomic
  • Pharmacokinetics
  • Polymorphisms
  • Renal clearance
  • Tubular secretion

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