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Abstract

In vitro metabolism of the novel antiinflammatory agent 6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thiazole.

M O Howard, J F Newton, D J Keohane, L P Yodis, C M Saverino, C W Qualls Jr and L W Schwartz
Drug Metabolism and Disposition September 1990, 18 (5) 607-612;
M O Howard
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J F Newton
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D J Keohane
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L P Yodis
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C M Saverino
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C W Qualls Jr
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L W Schwartz
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Abstract

6-(4'-Fluorophenyl)-5-(4'-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)

 

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Drug Metabolism and Disposition
Vol. 18, Issue 5
1 Sep 1990
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Abstract

In vitro metabolism of the novel antiinflammatory agent 6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thiazole.

M O Howard, J F Newton, D J Keohane, L P Yodis, C M Saverino, C W Qualls and L W Schwartz
Drug Metabolism and Disposition September 1, 1990, 18 (5) 607-612;

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Abstract

In vitro metabolism of the novel antiinflammatory agent 6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thiazole.

M O Howard, J F Newton, D J Keohane, L P Yodis, C M Saverino, C W Qualls and L W Schwartz
Drug Metabolism and Disposition September 1, 1990, 18 (5) 607-612;
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