| Autor: |
Varma, MV, Kimoto, E, Scialis, R, Bi, Y, Lin, J, Eng, H, Kalgutkar, AS, El‐Kattan, AF, Rodrigues, AD, Tremaine, LM |
| Předmět: |
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| Zdroj: |
Clinical Pharmacology & Therapeutics; Mar2017, Vol. 101 Issue 3, p406-415, 10p |
| Abstrakt: |
Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems. Single-dose rifampicin, an OATP inhibitor, decreased montelukast clearance in rats and monkeys. Clinical DDIs of montelukast were evaluated using physiologically based pharmacokinetic modeling; and simulation of the interactions with gemfibrozil-CYP2C8 and OATP1B1/1B3 inhibitor, clarithromycin-CYP3A and OATP1B1/1B3 inhibitor, and itraconazole-CYP3A inhibitor, implicated OATPs-CYP2C8-CYP2C8 interplay as the primary determinant of montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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