Evaluation of Renal Transporter Inhibition Using Creatinine as a Substrate In Vitro to Assess the Clinical Risk of Elevated Serum Creatinine

Creatinine is a widely accepted biomarker for renal toxicity, but its renal clearance via transporter-mediated active secretion is significant. For a given new chemical entity, therefore, elevations in serum creatinine (SCr) can be caused by the inhibition of renal transporter(s) without renal toxicity. In the present study, an effort was made to assess the correlation between the inhibition of renal transporters in vitro and elevations in SCr. A total of 15 compounds were chosen based on their known effect on SCr and minimal impact on glomerular filtration rate. Their inhibition potencies against the major creatinine renal transporters, including organic cation transporter 2, organic anion transporter 2, and 2 forms of multidrug and toxin extrusion (MATE1 and MATE2K), were assessed in transporter-transfected cell lines using creatinine as a probe substrate. Collectively, the data suggest that the observed elevations in SCr can be attributed to the inhibition of renal transporter(s), but inhibition of renal transporters does not necessarily lead to elevated SCr. Thus, renal transporter inhibition data can be used to rationalize SCr changes. Additionally, differing renal transporter inhibition potencies using creatinine and metformin as probe substrates suggest that substrate-dependent inhibition exists for some compounds.