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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??M 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.

SUBMITTER: Lepist EI

PROVIDER: S-EPMC4120670 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.

Lepist Eve-Irene EI Zhang Xuexiang X Hao Jia J Huang Jane J Kosaka Alan A Birkus Gabriel G Murray Bernard P BP Bannister Roy R Cihlar Tomas T Huang Yong Y Ray Adrian S AS

Kidney international 20140319 2

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 phy ...[more]

PMID: 24646860

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Project description:BackgroundPrior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts.MethodsTo fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time.ResultsObserved CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories.ConclusionsThese data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR.

Project description:Modulation of the transport-mediated active uptake by human serum albumin (HSA) for highly protein-bound substrates has been reported and improved the in vitro-to-in vivo extrapolation (IVIVE) of hepatic clearance. However, evidence for the relevance of such a phenomenon in the case of renal transporters is sparse. In this study, transport of renal organic anion transporter 1 or 3 (OAT1/3) substrates into conditionally immortalized proximal tubular epithelial cells transduced with OAT1/3 was measured in the presence and absence of 1 and 4% HSA while keeping the unbound substrate concentration constant (based on measured fraction unbound, fu,inc). In the presence of 4% HSA, the unbound intrinsic active uptake clearance (CLint,u,active) of six highly protein-bound substrates increased substantially relative to the HSA-free control (3.5- to 122-fold for the OAT1 CLint,u,active, and up to 28-fold for the OAT3 CLint,u,active). The albumin-mediated uptake effect (fold increase in CLint,u,active) was more pronounced with highly bound substrates compared to no effect seen for weakly protein-bound substrates adefovir (OAT1-specific) and oseltamivir carboxylate (OAT3-specific). The relationship between OAT1/3 CLint,u,active and fu,inc agreed with the facilitated-dissociation model; a relationship was established between the albumin-mediated fold change in CLint,u,active and fu,inc for both the OAT1 and OAT3, with implications for IVIVE modeling. The relative activity factor and the relative expression factor based on global proteomic quantification of in vitro OAT1/3 expression were applied for IVIVE of renal clearance. The inclusion of HSA improved the bottom-up prediction of the level of OAT1/3-mediated secretion and renal clearance (CLsec and CLr), in contrast to the underprediction observed with the control (HSA-free) scenario. For the first time, this study confirmed the presence of the albumin-mediated uptake effect with renal OAT1/3 transporters; the extent of the effect was more pronounced for highly protein-bound substrates. We recommend the inclusion of HSA in routine in vitro OAT1/3 assays due to considerable improvements in the IVIVE of CLsec and CLr.

Dataset Information

Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.

Publications

Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.

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