Potential of pranlukast and zafirlukast in the inhibition of human liver cytochrome P450 enzymes.
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).
Liu
K H
KH
Department of Pharmacology and Pharmacogenetics Research Center, Inje University College of Medicine Busan Paik Hospital, Korea.
Lee
Y M
YM
Shon
J H
JH
Kim
M J
MJ
Lee
S S
SS
Yoon
Y R
YR
Cha
I J
IJ
Shin
J G
JG
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*
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