Abstract
In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2 (OAT2), and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance (CLcr) is routinely used as a marker for acute kidney injury (AKI). Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors such as diet and disease state. Distinction between these possibilities is important from a drug development perspective as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, in order to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in depth in vitro-in vivo correlation analysis was conducted for sixteen drugs with in house and literature in vitro transporter inhibition data for OCT2, MATE1 and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic.
- drug-drug interactions
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- in vitro-in vivo prediction (IVIVE)
- kidney/renal
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics