ArticleThe Journal of pharmacology and experimental therapeutics2016
Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis.
Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 13 citations in OpenAlex.
- Nonalcoholic steatohepatitis increases plasma retention of sorafenib-glucuronide in a mouse model by altering hepatocyte hopping.Acta pharmaceutica Sinica. B · 2024Article
- Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease.Cells · 2021Review
- Interaction of Oatp1b2 expression and nonalcoholic steatohepatitis on pravastatin plasma clearance.Biochemical pharmacology · 2020Article
- Gene-by-Environment Interaction of BcrpDrug metabolism and disposition: the biological fate of chemicals · 2018Article
- Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis.Journal of biochemical and molecular toxicology · 2018Article
- Asking the Right Questions With Animal Models: Methionine- and Choline-Deficient Model in Predicting Adverse Drug Reactions in Human NASH.Toxicological sciences : an official journal of the Society of Toxicology · 2018Article
- Effect of Liver Disease on Hepatic Transporter Expression and Function.Journal of pharmaceutical sciences · 2017Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Hepatic multidrug resistance-associated protein 2 (MRP2) provides the biliary elimination pathway for many xenobiotics. Disruption of this pathway contributes to retention of these compounds and may ultimately lead to adverse drug reactions. MRP2 mislocalization from the canalicular membrane has been observed in nonalcoholic steatohepatitis (NASH), the late stage of nonalcoholic fatty liver disease, which is characterized by fat accumulation, oxidative stress, inflammation, and fibrosis. MRP2/Mrp2 mislocalization is observed in both human NASH and the rodent methionine and choline-deficient (MCD) diet model, but the extent to which it impacts overall transport capacity of MRP2 is unknown. Pemetrexed is an antifolate chemotherapeutic indicated for non-small cell lung cancer, yet its hepatobiliary elimination pathway has yet to be determined. The purpose of this study was to quantify the loss of Mrp2 function in NASH using an obligate Mrp2 transport substrate. To determine whether pemetrexed is an obligate Mrp2 substrate, its cumulative biliary elimination was compared between wild-type and Mrp2(-/-) rats. No pemetrexed was detected in the bile of Mrp2(-/-) rats, indicating pemetrexed is completely reliant on Mrp2 function for biliary elimination. Comparing the biliary elimination of pemetrexed between MCD and control animals identified a transporter-dependent decrease in biliary excretion of 60% in NASH. This study identifies Mrp2 as the exclusive biliary elimination mechanism for pemetrexed, making it a useful in vivo probe substrate for Mrp2 function, and quantifying the loss of function in NASH. This mechanistic feature may provide useful insight into the impact of NASH on interindividual variability in response to pemetrexed.
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