Abstract
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)
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|