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Excretion of creatinine is accomplished by filtration at the glomerulus (~85%) and secretion by the renal tubules (~15%). Numerous compounds cause elevations in serum creatinine. Clinical increases in serum creatinine result from renal cell toxicity or inhibition of creatinine transport by renal proximal tubules. Cellular toxicity can be verified by histology from a kidney biopsy or assessed by concomitant changes to urinary kidney injury protein biomarkers [99]. A mathematical method to predict inhibition of creatinine transport as a mechanism for elevations in serum creatinine has been published [100]. Expected changes to serum creatinine and creatinine clearance in healthy subjects based on available in vitro studies of several non‐nephrotoxic compounds that were MATE1 inhibitors (and reported IC₅₀ values) were incorporated. Given the localization of organic anion transporters (OAT) and OCT uptake transporters at the basolateral membrane of proximal tubules, IC₅₀ values for each compound were reported for these transporters as well. Increases in serum creatinine were found to be sensitive to MATE transporters for cimetidine, famotidine, ondansetron, ranolazine, trimethoprim, and vandetanib.

PBPK modeling was used to investigate serum creatinine increases that are routinely observed in clinical studies and treatments [101]. The model included inhibition of tubular secretion of creatinine by trimethoprim through OCT2, OCT3, MATE1, and MATE2‐K. Relative contribution of the transporters was calculated from published data. Transport activity of creatinine at the basolateral and apical membranes of proximal tubules and available protein expression in pooled human kidney microsomes was included. Inhibition constant (K _i ) values of 86.8 mmol/l (OCT2), 3.42 mmol/l (MATE1), and 2.16 mmol/l (MATE2‐K) were used. The model was validated with clinical data sets from single and multiple doses of trimethoprim. The pharmacokinetic model of creatinine included tubular secretion from each of the transporters. The model successfully predicted serum creatinine increases at three trimethoprim dosage regimens: 5 mg/kg intravenous twice daily (29%), 5 mg/kg intravenous four times daily (40%), 200 mg oral twice daily (26%). Development and validation of models, such as these two published ones, may better inform about expected changes to creatinine to obviate the concern of toxicity raised with increases in serum creatinine. Robust models may also reduce the need for some preclinical assessments.