Biological and Pharmaceutical Bulletin · 2009 · 11 citations · 11 references
MedicinePharmacokineticsPharmacologyDrug MetabolismHepatic PharmacokineticsMetabolismCytochrome P450 EnzymesCytochrome P450 InteractionsCytochrome P450-mediated MetabolismDrug-drug Interactions In MetabolismEnzyme InhibitionHepatic Drug MetabolismCyp3a4 InteractionsCyp450-mediated InteractionsCytochrome P450 3A4 MetabolismCytochrome P450 Drug MetabolismCytochrome P450 Enzyme ActivityCytochrome P450 Enzyme InhibitionCytochrome P450 Human Liver MicrosomesHepatic Drug-drug Interactions
We investigated the metabolism of pranlukast, a selective leukotriene agonist, and the potential for drug-drug interactions. Although cytochrome P450 (CYP) 3A4 appeared to be the major cytochrome P450 isoform involved in the metabolism of pranlukast, the results suggested that pranlukast metabolism was inhibited less than 50% by ketoconazole, a reversible CYP3A4 inhibitor, or by anti-CYP3A4 antibodies. Irreversible macrolide CYP3A4 inhibitors, clarithromycin, erythromycin and roxithromycin, exhibited little effect on pranlukast metabolism. On the other hand, pranlukast reversibly inhibited CYP2C8 and/or 2C9, and CYP3A4, with K(i) values of 3.9 and 4.1 micromol/l, respectively. The [I](in,max,u)/K(i) ratios were 0.004 and 0.003, respectively. The K(i) values were about 300-fold greater than the [I](in,max,u), therefore it is suggested that, at clinical doses, pranlukast will not affect the pharmacokinetics of concomitantly administered drugs that are primarily metabolized by CYP2C8 and/or 2C9 or CYP3A4.
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