Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8)

Sook Wah Yee; Anh Nguyet Nguyen; Chaline Brown; Radojka M. Savic; Youcai Zhang; Richard A. Castro; Cheryl D. Cropp; Ji Ha Choi; Diment Singh; Harunobu Tahara; Sophie L. Stocker; Yong Huang; Claire M. Brett; Kathleen M. Giacomini

doi:10.1002/jps.23581

Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8)

Sook Wah Yee, Anh Nguyet Nguyen, Chaline Brown, Radojka M. Savic, Youcai Zhang, Richard A. Castro, Cheryl D. Cropp, Ji Ha Choi, Diment Singh, Harunobu Tahara, Sophie L. Stocker, Yong Huang, Claire M. Brett, Kathleen M. Giacomini

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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, V_max, [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 (K_m) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CL_R; 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 (CL_sec) 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 CL_R and CL_sec.

Original language	English
Pages (from-to)	3451-3457
Number of pages	7
Journal	Journal of Pharmaceutical Sciences
Volume	102
Issue number	9
DOIs	https://doi.org/10.1002/jps.23581
State	Published - Sep 2013

Bibliographical note

Funding 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.

Keywords

Cefotaxime
OAT3
Organic anion transporter
Pharmacogenomic
Pharmacokinetics
Polymorphisms
Renal clearance
Tubular secretion

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10.1002/jps.23581

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Yee, S. W., Nguyen, A. N., Brown, C., Savic, R. M., Zhang, Y., Castro, R. A., Cropp, C. D., Choi, J. H., Singh, D., Tahara, H., Stocker, S. L., Huang, Y., Brett, C. M., & Giacomini, K. M. (2013). Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8). Journal of Pharmaceutical Sciences, 102(9), 3451-3457. https://doi.org/10.1002/jps.23581

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title = "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.",

keywords = "Cefotaxime, OAT3, Organic anion transporter, Pharmacogenomic, Pharmacokinetics, Polymorphisms, Renal clearance, Tubular secretion",

author = "Yee, {Sook Wah} and Nguyen, {Anh Nguyet} and Chaline Brown and Savic, {Radojka M.} and Youcai Zhang and Castro, {Richard A.} and Cropp, {Cheryl D.} and Choi, {Ji Ha} and Diment Singh and Harunobu Tahara and Stocker, {Sophie L.} and Yong Huang and Brett, {Claire M.} and Giacomini, {Kathleen M.}",

note = "Funding 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. ",

year = "2013",

month = sep,

doi = "10.1002/jps.23581",

language = "English",

volume = "102",

pages = "3451--3457",

journal = "Journal of Pharmaceutical Sciences",

issn = "0022-3549",

publisher = "Elsevier B.V.",

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T1 - Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8)

AU - Yee, Sook Wah

AU - Nguyen, Anh Nguyet

AU - Brown, Chaline

AU - Savic, Radojka M.

AU - Zhang, Youcai

AU - Castro, Richard A.

AU - Cropp, Cheryl D.

AU - Choi, Ji Ha

AU - Singh, Diment

AU - Tahara, Harunobu

AU - Stocker, Sophie L.

AU - Huang, Yong

AU - Brett, Claire M.

AU - Giacomini, Kathleen M.

N1 - Funding 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.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Cefotaxime

KW - OAT3

KW - Organic anion transporter

KW - Pharmacogenomic

KW - Pharmacokinetics

KW - Polymorphisms

KW - Renal clearance

KW - Tubular secretion

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U2 - 10.1002/jps.23581

DO - 10.1002/jps.23581

M3 - Article

C2 - 23649425

AN - SCOPUS:84881614134

SN - 0022-3549

VL - 102

SP - 3451

EP - 3457

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

IS - 9

ER -

Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8)

Abstract

Bibliographical note

Keywords

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