@article {Howard607, author = {M O Howard and J F Newton and D J Keohane and L P Yodis and C M Saverino and C W Qualls, Jr and L W Schwartz}, title = {In vitro metabolism of the novel antiinflammatory agent 6-(4{\textquoteright}-fluorophenyl)-5-(4{\textquoteright}-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thiazole.}, volume = {18}, number = {5}, pages = {607--612}, year = {1990}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {6-(4{\textquoteright}-Fluorophenyl)-5-(4{\textquoteright}-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thia zole (SK\&F 86002) is a dual inhibitor of arachidonic acid metabolism which has therapeutic potential for the treatment of inflammatory diseases. Previous studies in rats, in vivo, demonstrated that SK\&F 86002 metabolism proceeds by sequential steps of sulfur and nitrogen oxidation. Therefore, these studies were designed to 1) identify the enzymes (flavin vs. cytochrome P-450-dependent monooxygenases) which were responsible for SK\&F 86002 metabolism in vitro in hepatic microsomal suspensions from Sprague-Dawley rats, 2) characterize sex-dependent differences, and 3) quantitate the effect of pretreatment with SK\&F 86002. All three steps in the sequential metabolism of SK\&F 86002 to the N-oxide sulfone metabolite were quantitated individually. The three oxidation steps appeared to be catalyzed primarily by cytochrome P-450; heat inactivation (used to destroy flavin monooxygenase) had little effect on the metabolism of each compound. Further,N-octylamine failed to stimulate the metabolism of any compound and the cytochrome P-450 inhibitors (SK\&F 525-A, metyrapone, and alpha-naphthoflavone) resulted in a marked inhibition of the metabolism of all three substrates. Maximal velocities for metabolism of all three substrates (SK\&F 86002, sulfoxide, and sulfone) in microsomes isolated from male rats, were 3- to 5-fold greater than observed in female rats. Furthermore, pretreatment of male rats with SK\&F 86002 (60 mg/kg/day for 3 days) resulted in a change in the in vitro metabolism of all three substrates generally characterized by an increase in Vmax and/or a fall in km.(ABSTRACT TRUNCATED AT 250 WORDS)}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/18/5/607}, eprint = {https://dmd.aspetjournals.org/content/18/5/607.full.pdf}, journal = {Drug Metabolism and Disposition} }