Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity
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 nonalcohol...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521002100 |
| _version_ | 1819172451383246848 |
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| author | Joseph L. Jilek Kayla L. Frost Kevyn A. Jacobus Wenxi He Erica L. Toth Michael Goedken Nathan J. Cherrington |
| author_facet | Joseph L. Jilek Kayla L. Frost Kevyn A. Jacobus Wenxi He Erica L. Toth Michael Goedken Nathan J. Cherrington |
| author_sort | Joseph L. Jilek |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T20:07:23Z |
| format | Article |
| id | doaj.art-af1ce66f316a49febc4c7e9ade3a64d2 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-22T20:07:23Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-af1ce66f316a49febc4c7e9ade3a64d22022-12-21T18:14:06ZengElsevierActa Pharmaceutica Sinica B2211-38352021-12-01111238693878Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicityJoseph L. Jilek0Kayla L. Frost1Kevyn A. Jacobus2Wenxi He3Erica L. Toth4Michael Goedken5Nathan J. Cherrington6Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USARutgers Translational Sciences, Rutgers University, Piscataway, NJ 08901, USADepartment of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA; Corresponding author. Tel.: +1 520 626 0219.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.http://www.sciencedirect.com/science/article/pii/S2211383521002100Nonalcoholic steatohepatitisNASHCisplatinDrug transporterNephrotoxicity |
| spellingShingle | Joseph L. Jilek Kayla L. Frost Kevyn A. Jacobus Wenxi He Erica L. Toth Michael Goedken Nathan J. Cherrington Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity Acta Pharmaceutica Sinica B Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity |
| title | Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity |
| title_full | Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity |
| title_fullStr | Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity |
| title_full_unstemmed | Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity |
| title_short | Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity |
| title_sort | altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity |
| topic | Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521002100 |
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