Transport of the coumarin metabolite 7-hydroxycoumarin glucuronide is mediated via multidrug resistance-associated proteins 3 and 4.
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Publication year
2012Source
Drug Metabolism and Disposition, 40, 6, (2012), pp. 1076-9ISSN
Annotation
01 juni 2012
Publication type
Article / Letter to editor
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Organization
Pharmacology-Toxicology
IMM - Institute for Molecules and Materials
Journal title
Drug Metabolism and Disposition
Volume
vol. 40
Issue
iss. 6
Page start
p. 1076
Page end
p. 9
Subject
NCEBP 14: Cardiovascular diseases; NCMLS 5: Membrane transport and intracellular motility IGMD 9: Renal disorder; NCMLS 5: Membrane transport and intracellular motility N4i 3: Poverty-related infectious diseasesAbstract
Coumarin (1,2-benzopyrone) is a natural compound that has been used as a fragrance in the food and perfume industry and could have therapeutic usefulness in the treatment of lymphedema and different types of cancer. Several previous pharmacokinetic studies of coumarin have been performed in humans, which revealed extensive first-pass metabolism of the compound. 7-Hydroxycoumarin (7-HC) and its glucuronide (7-HC-G) are the main metabolites formed in humans, and via this route, 80 to 90% of the absorbed coumarin is excreted into urine, mainly as 7-HC-G. Active transport processes play a role in the urinary excretion of 7-HC-G; however, until now, the transporters involved remained to be elucidated. In this study, we investigated whether the efflux transporters multidrug resistance-associated proteins (MRP)1-4, breast cancer resistance protein, or P-glycoprotein play a role in 7-HC and 7-HC-G transport. For this purpose, we measured uptake of the metabolites into membrane vesicles overexpressing these transporters. Our results showed that 7-HC is not transported by any of the efflux transporters tested, whereas 7-HC-G was a substrate of MRP3 and MRP4. These results are in line with the pharmacokinetic profile of coumarin and suggest that MRP3 and MRP4 are the main transporters involved in the excretion of the coumarin metabolite 7-HC-G from liver and kidney.
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