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

J Pharm Sci. 2013 Sep;102(9):3451-7. doi: 10.1002/jps.23581. Epub 2013 May 6.

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 CL(sec) .

Keywords: OAT3; cefotaxime; organic anion transporter; pharmacogenomic; pharmacokinetics; polymorphisms; renal clearance; tubular secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anti-Bacterial Agents / blood*
  • Anti-Bacterial Agents / metabolism*
  • Asian Continental Ancestry Group / genetics
  • Cefotaxime / blood*
  • Cefotaxime / metabolism*
  • Female
  • Gene Frequency
  • HEK293 Cells
  • Humans
  • Kidney / metabolism*
  • Male
  • Organic Anion Transporters, Sodium-Independent / genetics*
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Polymorphism, Genetic
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Organic Anion Transporters, Sodium-Independent
  • organic anion transport protein 3
  • Cefotaxime