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 CLsec.

What do drug transporters really do?

“…In addition, coding or non-coding single-nucleotide polymorphisms (SNPs) that result in clinical phenotypes have been reported for SLC22A6 and SLC22A8 (REFS 39,64,78) (TABLE 2). Although more extensive phenotypic analyses of the effects of OAT SNPs needs to be performed, these limited studies seem to be consistent with the in vitro and in vivo knockout data on their role in drug and toxin handling.…”

“…Although more extensive phenotypic analyses of the effects of OAT SNPs needs to be performed, these limited studies seem to be consistent with the in vitro and in vivo knockout data on their role in drug and toxin handling. For example, polymorphisms in SLC22A6 ( OAT1 ) and/or SLC22A8 ( OAT3 ) have been associated with mercury toxicity 64 , response to diuretics and antibiotic-handling capacity 39,78 . Nevertheless, given their obvious importance in drug handling, it is somewhat surprising that more evidence has not yet emerged for SNPs in SLC22A6 and SLC22A8 that affect drug disposition.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Polymorphisms in OAT1, OAT3, and MRP2 are more common among miners exhibiting toxicity from mercury-containing vapors (50). Additionally, OAT3 polymorphisms have been associated with altered cephalosporin handling (87), and suggestive evidence indicates the possible involvement of OATs in antiviral and methotrexate elimination (88,89). One of the better-studied examples of drug transporter polymorphisms affecting renal drug elimination is that of OCT2 (SLC22A2).…”

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

“…This can be explained by the narrow range of creatinine values; in addition, it is well-known that creatinine is not the best predictor of renal function in neonates, partly because of the influence of residual maternally derived creatinine (33,34). The potential role of transporters in renal clearance will also have to be investigated in further studies (35). The optimization of dosing for antimicrobial therapy should take into consideration developmental pharmacokinetics-pharmacodynamics, microbiology, and safety (36,37).…”