Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring.
The metabolic transformation of the antibronchospastic compound ABC-99 [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] was studied in vitro with a rat liver microsomal preparation containing an NADPH-generating system. Thirty percent of the ABC-99 was metabolized and the only metabolic pathway observed as the oxidation of the 1,3-dithiolane ring. Two distinct sulfoxides were formed diastereoselectively, the trans isomer being the major product in the ratio 7:3. In contrast to the 1,3-dioxolane ring of doxophylline, the 1,3-dithiolane ring of ABC-99 did not undergo oxidative opening through acetal carbon oxidation. Furthermore no N-dealkylation to theophylline was observed. This high regioselectivity in in vitro metabolism was most likely due to the nucleophilicity of the sulfur atom. The diastereoselective sulfoxidation was apparently catalyzed by flavin-dependent monooxygenases, as no effect was observed with CO treatment, whereas selective thermal inactivation significantly reduced the rate of sulfoxidation.
Grosa
G
G
Istituto di Chimica Farmaceutica Applicata, Università di Torino, Italy.
Caputo
O
O
Ceruti
M
M
Biglino
G
G
Franzone
J S
JS
Cravanzola
C
C
D000818:Animals; D000996:Antitussive Agents / Q000378:metabolism; D001993:Bronchodilator Agents / Q000032:analysis / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013454:Sulfoxides / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
D000996:Antitussive Agents; D001993:Bronchodilator Agents; D013454:Sulfoxides; C068410:ABC 99; D013806:Theophylline; C029797:doxofylline