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.
Bibliographical noteFunding Information:
This work was supported by a grant from the National Institutes of Health (NIH; GM61390). C.B. was supported by National Research Service Award T32 GM07546 from the NI H. This work was also made possible in part by core services provided by the Clinical and Translational Science Institute (CTSI), Clinical Research Center at San Francisco General Hospital, funded by the National Center for Research Resources (NIH MO1-RR00083-44). We thank all staff at UCSF Drug Studies Unit for developing the analytical procedure for determining cefotaxime in clinical samples. We thank Howard Horng and Kari Morrissey for their guidance to develop the analytical method for determining cefotaxime in cell lines.
- Organic anion transporter
- Renal clearance
- Tubular secretion