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Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

Joseph L Jilek1, Kayla L Frost1, Kevyn A Jacobus1

  • 1Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA.

Acta Pharmaceutica Sinica. B
|January 13, 2022
PubMed

Insights

Nonalcoholic steatohepatitis (NASH) in rats reduced cisplatin (CDDP) nephrotoxicity by altering drug transporters. NASH decreased CDDP renal clearance and accumulation, potentially protecting kidneys from CDDP-induced damage.

Area of Science:

  • Pharmacology and Toxicology
  • Hepatology
  • Nephrology

Background:

  • Disease states significantly alter drug disposition, leading to adverse drug reactions.
  • Cisplatin (CDDP) nephrotoxicity arises from proximal tubule cell exposure during renal secretion.
  • Nonalcoholic steatohepatitis (NASH) alters renal drug transporter expression, but its effect on CDDP toxicity is unknown.

Purpose of the Study:

  • To investigate NASH-associated changes in CDDP pharmacokinetics, transporter expression, and toxicity.
  • To determine if NASH influences CDDP-induced nephrotoxicity.

Main Methods:

  • A methionine- and choline-deficient diet induced NASH in a rat model.
  • NASH and healthy control rats were administered CDDP (6 mg/kg, i.p.).
  • Evaluated CDDP pharmacokinetics, renal and hepatic transporter expression, and nephrotoxicity.

Main Results:

  • NASH rats exhibited 20% less CDDP-induced nephrotoxicity compared to healthy rats.
  • CDDP renal clearance and secretion decreased significantly in NASH rats, reducing renal accumulation by 15%.
  • Altered expression of renal transporters (decreased Copper Transporter-1, increased Organic Cation Transporter-2 and ATP7b) correlated with reduced CDDP secretion.
  • Hepatic CDDP accumulation increased 250% in NASH rats due to transporter changes, without observed hepatic toxicity.

Conclusions:

  • NASH significantly reduces CDDP nephrotoxicity by altering renal drug transporter expression and decreasing renal clearance.
  • Increased hepatic CDDP sequestration in NASH rats, mediated by hepatic transporter changes, may contribute to reduced renal toxicity.
  • These findings link NASH-induced transporter alterations to modified CDDP disposition and nephrotoxicity.
Keywords:
ATP7, ATPase copper transporting proteinCDDP, cisplatinCTR, copper transporterCisplatinDDTC, diethyldithiocarbamateDT, drug transporterDrug transporterGFR, glomerular filtration rateLC–MS/MS, liquid chromatography–tandem mass spectrometryMATE, multidrug and toxin extrusion proteinMCD, methionine- and choline-deficient dietNAFLD, nonalcoholic fatty liver diseaseNASHNASH, nonalcoholic steatohepatitisNephrotoxicityNonalcoholic steatohepatitisOCT, organic cation transporterP-gp, p-glycoproteinPK, pharmacokinetics

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