Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)
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 v...
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Published in | Journal of pharmaceutical sciences Vol. 102; no. 9; pp. 3451 - 3457 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Elsevier Inc
01.09.2013
Wiley Subscription Services, Inc., A Wiley Company Elsevier Limited |
Subjects | |
Online Access | Get full text |
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Summary: | 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 |
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ISSN: | 0022-3549 1520-6017 |
DOI: | 10.1002/jps.23581 |