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Functional heterogeneity of polymorphisms in the human organic anion transporter, OAT3 (SLC22A8)
Author(s) -
Erdman A. R.,
Brown C.,
Castro R.,
Taylor T.,
Carlson E.,
Giacomini K. M.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.260
Subject(s) - organic anion transporter 1 , transporter , computational biology , biology , genetics , gene
Background The human organic anion transporter, OAT3 ( SLC22A8 ), mediates renal excretion of various drugs including cephalosporins. To test whether genetic variants of OAT3 exhibit altered function in vitro and in vivo , we conducted a series of studies. Methods Coding region variants of OAT3 were identified in an ethnically diverse population of 276 humans. Variants were constructed by site‐directed mutagenesis and expressed in human embryonic kidney cells. Cellular uptake of radiolabeled estrone sulfate (ES) was determined in the presence and absence of 5 mM cefotaxime. To evaluate in vivo variant function, subjects with selected alleles were given an IV dose of 2 gm cefotaxime and serial blood and urine cefotaxime concentrations were measured. Results We discovered 10 non‐synonymous OAT3 variants. In in vitro assays, three variants (F>L, A>S, V>I) showed minimally reduced (<33%) ES uptake; two (R>W, I>F) showed moderately reduced (33–66%) uptake; and four (R>S, Q>X, I>R, A>V) were non‐functional. Cefotaxime significantly inhibited ES uptake by all variants that retained function. Preliminary results of the in vivo trial show that two subjects (one heterozygous for I>F, and one with both Q>X and R>S alleles) had reduced cefotaxime renal clearance compared to two controls. Conclusions We identified a number of OAT3 variants with reduced function. Preliminary results suggest that individuals with these variants have reduced renal cefotaxime clearance. Clinical Pharmacology & Therapeutics (2005) 77 , P96–P96; doi: 10.1016/j.clpt.2004.12.260