Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)

• Published in: Journal of pharmaceutical sciences Vol. 102; no. 9; pp. 3451 - 3457
• Main Authors: Yee, Sook Wah, Nguyen, Anh Nguyet, Brown, Chaline, Savic, Radojka M., Zhang, Youcai, Castro, Richard A., Cropp, Cheryl D., Choi, Ji Ha, Singh, Diment, Tahara, Harunobu, Stocker, Sophie L., Huang, Yong, Brett, Claire M., Giacomini, Kathleen M.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.09.2013; Wiley Subscription Services, Inc., A Wiley Company; Elsevier Limited
• Subjects: Adolescent; Adult; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - metabolism; Asian Continental Ancestry Group - genetics; cefotaxime; Cefotaxime - blood; Cefotaxime - metabolism; Female; Gene Frequency; HEK293 Cells; Humans; Kidney - metabolism; Male; OAT3; organic anion transporter; Organic Anion Transporters, Sodium-Independent - genetics; Organic Anion Transporters, Sodium-Independent - metabolism; pharmacogenomic; pharmacokinetics; Polymorphism, Genetic; polymorphisms; renal clearance; tubular secretion; Young Adult; cefotaxime; renal clearance; OAT3; tubular secretion; organic anion transporter; pharmacokinetics; pharmacogenomic; polymorphisms
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.23581

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±3nmol*(mg protein)-1/min (mean±SD)] compared with the reference OAT3 [305±28nmol*(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±32.1mL/min, n=5) compared with volunteers that were homozygous for the reference allele (158±44.1mL/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±31.8mL/min (mean±SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0±42.2mL/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 .©2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3451–3457, 2013