In vitro microsomal metabolism of the leukotriene receptor antagonist, 5-(2-dodecylphenyl)-4,6-dithianonanedioic acid (SK&F 102,081).

ABSTRACT

In vivo experiments indicate that the major route of metabolism of SK&F 102,081 [5-(2-dodecylphenyl)-4,6-dithianonanedioic acid] is via omega-oxidation and subsequent beta-oxidation. Therefore, in vitro experiments were designed to characterize the initial reaction of this pathway, omega-hydroxylation. SK&F 102,081 was metabolized by rat hepatic microsomes to two products; mass spectral analysis indicated that these products were the omega (omega) and omega minus one (omega-1) hydroxylated metabolites, 5-[2-(12-hydroxy)dodecylphenyl]-4,6-dithianonanedioic acid and 5-[2-(11-hydroxy)dodecylphenyl]-4,6-dithianonanedioic acid, respectively. NADPH and oxygen were required for the formation of these metabolites. Kinetic analysis of omega- and (omega-1)-hydroxylations of SK&F 102,081 indicated that the apparent Km for (omega-1)-hydroxylation (52.6 microM) was approximately 2.5-fold higher than the apparent Km for omega-hydroxylation (22.0 microM). Furthermore, the cytochrome P-450 inhibitor, metyrapone, produced differential inhibition of omega- and (omega-1)-hydroxylation. In addition, the terminal acetylenic analogue of SK&F 102,081, SK&F 103,600 (5-[2-(11-dodecynyl)phenyl]-4,6-dithianonanedioic acid), produced differential suicide inactivation of SK&F 102,081 omega- and (omega-1)-hydroxylations. These studies indicate that the omega- and (omega-1)-hydroxylations of SK&F 102,081 are probably carried out by different isozymes of hepatic cytochrome P-450 in the rat. Furthermore, the isozymes that hydroxylate SK&F 102,081 at the omega- and (omega-1)-positions may be similar to those which mediate similar reactions on endogenous compounds such as prostaglandins and leukotrienes.