In vitro and in vivo biotransformations of the potent leukotriene D4 antagonist verlukast in the rat.
Verlukast, (S)3-((((3-(2-(7-chloroquinolin-2-yl)-(E)-ethenyl)phenyl)- 3-dimethylamino-3-oxopropylthio)methyl)thio)propionic acid, formerly known as MK-679, is a potent leukotriene D4 antagonist. Verlukast was incubated with rat liver microsomes under oxidative conditions to generate five metabolites, which were identified as the four possible isomeric monosulfoxides (M1-M4), and the N-hydroxymethyl amide (M5). This latter metabolite loses the elements of formaldehyde to yield the N-monomethyl amide (M6). These metabolites were isolated from a large microsomal incubation and were characterized by UV, 1H-NMR, and fast atom bombardment-MS. These data were identical to those obtained from synthetically prepared standards. Microsomal incubations of verlukast supplemented with UDP-glucuronic acid yielded the acyl glucuronide metabolite (M7), which was isolated and characterized by UV, 1H-NMR, and fast atom bombardment-M5. Verlukast was regenerated from M7 upon treatment with either beta-glucuronidase or strong aqueous base (pH greater than 11). The metabolites described above were all detected in bile collected from a rat dosed with verlukast.
Merck Frosst Centre for Therapeutic Research, Pointe-Claire, Quebec, Canada.
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D
Nicoll-Griffith
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J
Yergey
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L
Trimble
H
H
Williams
R
R
Rasori
R
R
Zamboni
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005966:Glucuronidase / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011422:Propionates / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013454:Sulfoxides / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D011422:Propionates; D011804:Quinolines; D013189:SRS-A; D013454:Sulfoxides; D014535:Uridine Diphosphate Glucuronic Acid; C059141:verlukast; D005966:Glucuronidase