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Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors.

Abstract：

:The purpose of this study was to elucidate the role of human organic anion transporters (human OATs) in the induction of drug-induced skeletal muscle abnormalities. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been clinically used for lowering plasma cholesterol levels, and are known to induce various forms of skeletal muscle abnormalities including myopathy and rhabdomyolysis. Immunohistochemical analysis revealed that human OAT1 and human OAT3 are localized in the cytoplasmic membrane of the human skeletal muscles. The activities of human OATs were measured using mouse cell lines from renal proximal tubules stably expressing human OATs. Human OAT3, but not human OAT1, mediates the transport of pravastatin. Fluvastatin inhibited organic anion uptake mediated by human OAT1 in a mixture of competitive and noncompetitive manner, whereas simvastatin and fluvastatin noncompetitively inhibited the organic anion uptake mediated by human OAT3. In conclusion, the organic anion transporters OAT1 and OAT3 are localized in the cytoplasmic membrane of human skeletal muscles. Pravastatin, simvasatin, and fluvasatin inhibit human OATs activity. These results suggest that muscle organic anion transporters play a role in the muscular side effects of HMG-CoA reductase inhibitors.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Takeda M,Noshiro R,Onozato ML,Tojo A,Hasannejad H,Huang XL,Narikawa S,Endou H

doi

10.1016/j.ejphar.2003.10.017

keywords:

subject

Has Abstract

pub_date

2004-01-12 00:00:00

pages

133-8

issue

2-3

eissn

0014-2999

issn

1879-0712

pii

S001429990302538X

journal_volume

483

pub_type

杂志文章

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