Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

Abstract

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions. Cisplatin (CDDP) elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion. Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis (NASH), however, associated changes to substrate toxicity is unknown. To test this, a methionine- and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics, transporter expression, and toxicity. NASH rats administered CDDP (6 mg/kg, i.p.) displayed 20% less nephrotoxicity than healthy rats. Likewise, CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min, renal secretion decreased from 6.23 to 2.80 mL/min, and renal CDDP accumulation decreased by 15%, relative to healthy rats. Renal copper transporter-1 expression decreased, and organic cation transporter-2 and ATPase copper transporting protein-7b increased slightly, reducing CDDP secretion. Hepatic CDDP accumulation increased 250% in NASH rats relative to healthy rats. Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats, although no drug-related toxicity was observed. These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance, which may alter nephrotoxicity.

Keywords: ATP7, ATPase copper transporting protein; CDDP, cisplatin; CTR, copper transporter; Cisplatin; DDTC, diethyldithiocarbamate; DT, drug transporter; Drug transporter; GFR, glomerular filtration rate; LC–MS/MS, liquid chromatography–tandem mass spectrometry; MATE, multidrug and toxin extrusion protein; MCD, methionine- and choline-deficient diet; NAFLD, nonalcoholic fatty liver disease; NASH; NASH, nonalcoholic steatohepatitis; Nephrotoxicity; Nonalcoholic steatohepatitis; OCT, organic cation transporter; P-gp, p-glycoprotein; PK, pharmacokinetics.