title: Potential of pranlukast and zafirlukast in the inhibition of human liver cytochrome P450 enzymes.
abstract: 1. The potential of zafirlukast to inhibit several human cytochrome P450 enzymes is well known. However, pranlukast, a structural analogue of zafirlukast, has not been studied. Accordingly, the inhibitory potential of pranlukast was evaluated and compared with that of zafirlukast, a known CYP2C9 inhibitor, in in vitro microsomal incubation studies. 2. Both pranlukast and zafirlukast showed moderate inhibition of CYP2C9-catalysed tolbutamide 4-methylhydroxylation, competitively inhibiting tolbutamide 4-methylhydroxylation with estimated mean K(i) values of 3.82 +/- 0.50 and 5.86 +/- 0.08 microM, respectively. 3. Pranlukast had no effect on CYP2C19-catalysed S-mephenytoin 4'-hydroxylation or CYP3A4-catalysed midazolam 1-hydroxylation. However, zafirlukast showed minor inhibition of these reactions. Neither pranlukast nor zafirlukast inhibited CYP1A2-catalysed phenacetin O-deethylation, CYP2D6-catalysed dextromethorphan O-demethylation or CYP2E1-catalysed chlorzoxazone 6-hydroxylation. 4. The results suggest that like zafirlukast, pranlukast also has the potential moderately to inhibit CYP2C9-catalysed tolbutamide 4-methylhydroxylation. Therefore, the inhibitory potential of pranlukast should be considered when it is co-administered with CYP2C9 substrates with narrow therapeutic ranges (e.g. S-warfarin, phenytoin).
authors.affiliation: Department of Pharmacology and Pharmacogenetics Research Center, Inje University College of Medicine Busan Paik Hospital, Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Liu
authors.forename: Y M
authors.initials: YM
authors.lastname: Lee
authors.forename: J H
authors.initials: JH
authors.lastname: Shon
authors.forename: M J
authors.initials: MJ
authors.lastname: Kim
authors.forename: S S
authors.initials: SS
authors.lastname: Lee
authors.forename: Y R
authors.initials: YR
authors.lastname: Yoon
authors.forename: I J
authors.initials: IJ
authors.lastname: Cha
authors.forename: J G
authors.initials: JG
authors.lastname: Shin
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D002867:Chromones / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007211:Indoles; D007700:Kinetics; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D048448:Phenylcarbamates; D013449:Sulfonamides; D014044:Tolbutamide / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology*
chemical_list: D002867:Chromones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C047681:pranlukast; C062735:zafirlukast