title: Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8).
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) .
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.
authors: Sook Wah
authors: SW
authors: Yee
authors: Anh Nguyet
authors: AN
authors: Nguyen
authors: Chaline
authors: C
authors: Brown
authors: Radojka M
authors: RM
authors: Savic
authors: Youcai
authors: Y
authors: Zhang
authors: Richard A
authors: RA
authors: Castro
authors: Cheryl D
authors: CD
authors: Cropp
authors: Ji Ha
authors: JH
authors: Choi
authors: Diment
authors: D
authors: Singh
authors: Harunobu
authors: H
authors: Tahara
authors: Sophie L
authors: SL
authors: Stocker
authors: Yong
authors: Y
authors: Huang
authors: Claire M
authors: CM
authors: Brett
authors: Kathleen M
authors: KM
authors: Giacomini
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D002439:Cefotaxime / Q000097:blood* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D002439:Cefotaxime
keywords: OAT3; cefotaxime; organic anion transporter; pharmacogenomic; pharmacokinetics; polymorphisms; renal clearance; tubular secretion
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