Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)
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INTRODUCTION
OAT1 (SLC22A6) and OAT3 (SLC22A8) are well- studied organic anion transporters known to reabsorb and secrete endogenous organic anions (e.g., pyruvate, α-ketoglutarate, oxalate, urate, and estrone sulfate) and exogenous anions (e.g., methotrexate, ciprofloxacin, acyclovir, captopril, and thiazides) across the basolateral membrane of the proximal tubule.1., 2., 3., 4. In vivo studies in Oat3 knockout mice demonstrate the importance of OAT3 in the renal elimination of drugs. The area under the
RESULTS AND DISCUSSION
In vitro cefotaxime transport was measured using HEK293-Flp-in cells stably transfected with empty vector (EV), reference SLC22A8 cDNA or with OAT3- Ile305Phe variant cDNA, reference SLC22A6 (OAT1), SLC22A7 (OAT2), and SLC22A11 (OAT4) cDNA subcloned into the mammalian expression vector pcDNA5/FRT. These cell lines, which were previously generated in our laboratory,10., 24., 25., 26. took up radiolabeled model substrates of organic anion transporters (Fig. S1). Cefotaxime uptake studies were
CONCLUSIONS
Cefotaxime is a third-generation cephalosporin with broad-spectrum antibacterial activity. In this study, we show that cefotaxime is a substrate of OAT3 and that the low-frequency OAT3 variant, Ile305Phe, found in Asians (~ 3.5% allele frequency), is associated with significant reduced cefotaxime uptake and reduced Vmax in in vitro kinetic studies. Our cell surface biotinylation study suggests that the mechanism of the reduced cefotaxime Vmax in OAT3-Ile305Phe cells is because of lower surface
ACKNOWLEDGMENTS
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
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2021, Pharmacology and TherapeuticsCitation Excerpt :In HEK293 cells, the OAT3-Ile305Phe variant had a reduced maximum transport activity for cefotaxime, a substrate of OAT3 without affecting the Michaelis-Menten constant value of OAT3, and a significantly decreased surface expression of OAT3. As OAT3-Ile305Phe variant accounts for about 3.5% allele frequency in Asians, a clinical study showed that OAT3-Ile305Phe variant significantly suppressed the renal clearance of cefotaxime, in healthy volunteers (Yee et al., 2013). Besides, a SNP (Position at chromosome11: 64088038, A/G) of OAT4 was associated with renal underexcretion type gout by analysis of OAT4 gene in gout patients and healthy volunteers, suggesting that OAT4 expressed at apical membrane of renal proximal tubule cells contributed to urate transport in humans (Kolz et al., 2009; Sakiyama et al., 2014).
In vitro characterization of zebrafish (Danio rerio) organic anion transporters Oat2a-e
2018, Toxicology in VitroCitation Excerpt :Human OAT2 was shown to transport a number of pharmacologically active agents, and has been increasingly recognized in terms of its role in drug disposition (Shen et al., 2016). Out of these four pharmaceuticals, three have been well characterized as substrates of human OAT2: erythromycin and tetracycline (Babu et al., 2002, Kobayashi et al., 2005, Yee et al., 2013), and diclofenac (Zhang et al., 2016). Indomethacin has been identified as a potent inhibitor of human OAT2 (IC50 values 2.1 to 6.5 μM) (Shen et al., 2015, Zhang et al., 2015), OAT1 (IC50 values 3 to 10 μM), and OAT3 (IC50 values 0.61 to 5.95 μM) (Khamdang et al., 2002).
Single nucleotide polymorphisms of ABCC2 modulate renal secretion of endogenous organic anions
2017, Biochemical PharmacologyCitation Excerpt :The typical pattern observed in these patients is an increased urinary secretion of coproporphyrin isomer I as a result of impaired biliary secretion [14,15]. SNPs in the genes encoding tubular transporters were shown to alter the renal excretion of xenobiotics (e.g., cephalosporins [16], methotrexate [17,18], metformin [19] or environmental toxins [20]). Logically, such SNPs may also affect the net transport of endogenous metabolites from blood to urine.
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