title: Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.
abstract: Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition.
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Eve-Irene
authors.initials: EI
authors.lastname: Lepist
authors.affiliation: Optivia Biotechnology, Menlo Park, California, USA.
authors.forename: Xuexiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Hao
authors.affiliation: Optivia Biotechnology, Menlo Park, California, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Huang
authors.affiliation: Optivia Biotechnology, Menlo Park, California, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kosaka
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Murray
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Bannister
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.affiliation: Optivia Biotechnology, Menlo Park, California, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D000069547:Cobicistat; D003404:Creatinine / Q000097:blood* / Q000378:metabolism*; D003412:Cricetulus; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011994:Recombinant Proteins / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D000099254:Organic Cation Transporter 3
chemical_list: D002219:Carbamates; D002927:Cimetidine; D000069547:Cobicistat; D003404:Creatinine; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011994:Recombinant Proteins; D013844:Thiazoles; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human; C490280:SLC22A7 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human