PT  - JOURNAL ARTICLE
AU  - D A Nicoll-Griffith
AU  - N Chauret
AU  - J A Yergey
AU  - L A Trimble
AU  - L Favreau
AU  - R Zamboni
AU  - S J Grossman
AU  - J Drey
AU  - E Herold
TI  - Characterization of verlukast metabolites arising from an epoxide intermediate produced with hepatic microsomes from beta-naphthoflavone-treated rodents (P-4501A1).
DP  - 1993 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 861--867
VI  - 21
IP  - 5
4099  - http://dmd.aspetjournals.org/content/21/5/861.short
4100  - http://dmd.aspetjournals.org/content/21/5/861.full
SO  - Drug Metab Dispos1993 Sep 01; 21
AB  - Verlukast, (R)3-((((3-(2-(7-chloroquinolin-2-yl)-(E)-ethenyl)phenyl)-3- dimethylamino-3-oxopropylthio)methyl)thio)-propionic acid (also known as MK-0679 and L-668,019), is a potent leukotriene D4 antagonist. Verlukast was incubated with hepatic microsomes from beta-naphthoflavone (beta NF) or isosafrole-treated rodents to evaluate whether P-4501A1 or 1A2 mediated biotransformations could occur. With beta NF-induced mouse or rat microsomes, in which the induction of P-4501A1 had been proven by Western blot analysis, incubations produced new metabolites that were separated by reversed-phase HPLC and were initially characterized by UV (photodiode array). Metabolites were subsequently isolated and characterized by NMR and MS, and were assigned as the 5",6"-dihydrodiol and 6"-phenol (on the quinoline ring). The presumed 5",6"-epoxide intermediate was also detected and was characterized by UV (photodiode array) and MS. Microsomes from isosafrole-treated rodents produced the dihydrodiol to a much lesser extent and did not yield any other new metabolites. alpha-Naphthoflavone inhibited the dihydrodiol formation in incubations with microsomes from isosafrole- and beta NF-treated rats. In incubations with microsomes from beta NF-treated rats, to which the epoxide hydrolase inhibitor 3,3,3-trichloropropene 1,2-oxide had been added, the formation of dihydrodiol was inhibited, consistent with a microsomal epoxide hydrolase hydrolysis of the epoxide intermediate. When glutathione was added to incubations with microsomes from beta NF-treated rats, the dihydrodiol, phenol, and epoxide peaks were reduced in size and a new material, the glutathione adduct, was formed.(ABSTRACT TRUNCATED AT 250 WORDS)