X. Zhang, W. Jiang, C. Li, J. Huang, Y. Huang; Optivia Biotechnology Inc, Menlo Park, CA

BACKGROUND: Serum creatinine (SCr) levels or creatinine clearance (CrCl) are commonly measured to estimate renal function in clinical practices. A number of drugs have been reported to affect SCr/CrCl without nephrotoxicity, attributed to the reduction of tubular creatinine secretion by inhibiting specific transporters. We have identified that OCT2, OAT2, OCT3, MATE1 and MATE2K are the major creatinine transporters, and established a novel creatinine secretion model by co-expressing the quintuple transporters in polarized MDCK-II cells. We explored whether an IVIVC exists between the clinical CrCl reduction by drugs and the inhibition of creatinine transport in our model.
METHODS: The inhibition of drugs from different therapeutic categories on the creatinine transport were measured at a wide range of concentrations including the clinical Cmax.
RESULTS: All drugs except probenecid (a negative control) attenuated the transcellular transport of creatinine. Inhibition at the clinical Cmax was quantified and correlated with the corresponding clinical CrCl reduction documented in literature, leading to the appearance of a clear IVIVC (Figure 1).
The quintuple-transporter model of creatinine tubular secretion can be a useful in vitro tool to evaluate and predict a drug’s effect on creatinine secretion in vivo.