Metabolism of the leukotriene receptor antagonist 5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid (SK&F 102922) in the guinea pig. Rearrangement of the acyl glucuronide.
A primary route of inactivation of leukotrienes and their receptor antagonists (LTRA) is metabolism by omega oxidation. SK&F 102922 [5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid] is a LTRA that was designed to be resistant to omega oxidation. Therefore, these experiments were designed to characterize the metabolic fate of [14C]SK&F 102922. Following iv administration of SK&F 102922 (5 mg/kg), 80% of injected radioactivity was excreted in bile in 1 hr. At least five metabolites and parent (18% of administered dose) were present in bile. One metabolite (M1), which accounted for less than 10% of the excreted radioactivity, was monohydroxylated. Three metabolites (M2, M3A, and M3B), which together accounted for greater than 50% of excreted radioactivity, had mass spectra consistent with acyl glucuronides. All three metabolites were alkali labile, whereas only one metabolite (M2) was susceptible to beta-glucuronidase hydrolysis. These data indicate that M3a and M3b are nonglycosidic isomers of M2 that were formed by a nonenzymic reaction involving migration of the aglycone (SK&F 102922) from C-1 to C-2, C-3, or C-4 of glucuronic acid. The 1-O-acyl-beta-glucuronide of SK&F 102922 (M2) exhibits pH dependent rearrangement, with half-lives ranging from 1 to greater than 1000 hr. Therefore, acyl glucuronidation can account for much of the metabolic fate of SK&F 102922 and, potentially, other structurally related LTRAs or endogenous leukotrienes themselves.
Newton
J F
JF
Department of Drug Metabolism, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Straub
K M
KM
Dewey
R H
RH
Perchonock
C D
CD
McCarthy
M E
ME
Gleason
J G
JG
Lynn
R K
RK
D000818:Animals; D003998:Dicarboxylic Acids / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D011971:Receptors, Immunologic / Q000187:drug effects*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*
D003998:Dicarboxylic Acids; D005965:Glucuronates; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C046472:5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid