Biliary elimination of pemetrexed is dependent on Mrp2 in rats: Potential mechanism of variable response in nonalcoholic steatohepatitis

Anika L. Dzierlenga, John D. Clarke, David M. Klein, Tarun Anumol, Shane A Snyder, Hong Yu Li, Nathan J Cherrington

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 transporterdependent 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.

Original languageEnglish (US)
Pages (from-to)246-253
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume358
Issue number2
DOIs
StatePublished - Aug 1 2016

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Pemetrexed
Choline
Methionine
Folic Acid Antagonists
Xenobiotics
Non-alcoholic Fatty Liver Disease
Hepatobiliary Elimination
Drug-Related Side Effects and Adverse Reactions
Bile
Non-Small Cell Lung Carcinoma
Rodentia
Oxidative Stress
Fibrosis
Fats
Diet
Inflammation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Biliary elimination of pemetrexed is dependent on Mrp2 in rats : Potential mechanism of variable response in nonalcoholic steatohepatitis. / Dzierlenga, Anika L.; Clarke, John D.; Klein, David M.; Anumol, Tarun; Snyder, Shane A; Li, Hong Yu; Cherrington, Nathan J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 358, No. 2, 01.08.2016, p. 246-253.

Research output: Contribution to journalArticle

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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 transporterdependent 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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