Metabolism of 7-(1,3-thiazolidin-2-ylmethyl)theophylline by rat liver microsomes. Evidence for a monooxygenase-dependent step in 1,3-thiazolidine ring cleavage.
Metabolic transformation of the mucoregulator and bronchodilator 7-(1,3-thiazolidin-2-ylmethyl)theophylline was studied in vitro with a rat liver microsomal preparation containing a NADPH-generating system. The only metabolite observed was 7-theophyllinacetaldehyde. In contrast to previous literature pointing out the chemical nature of 2-substituted thiazolidine ring cleavage, the formation of 7-theophyllinacetaldehyde was mediated by monooxygenase-dependent oxidation. Possibly an unstable sulfoxide was the first metabolic product, rapidly converted to 7-theophyllinacetaldehyde by hydrolysis. The sulfoxidation was apparently catalyzed mainly by flavin-containing monooxygenases, as selective thermal inactivation and methymazole significantly reduced the rate of formation of the metabolite. No N7-dealkylation pathway producing theophylline was detected, indicating a high regioselectivity in in vitro metabolism, due to the nucleophilicity of the sulfur atom.
Grosa
G
G
Istituto di Chimica Farmaceutica Applicata, Università di Torino, Italy.
Caputo
O
O
Ceruti
M
M
Biglino
G
G
D000818:Animals; D001993:Bronchodilator Agents / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D013806:Theophylline / Q000031:analogs & derivatives* / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism*; D053778:Thiazolidines
D001993:Bronchodilator Agents; D013844:Thiazoles; D053778:Thiazolidines; C078235:7-(1,3-thiazolidin-2-ylmethyl)theophylline; D013806:Theophylline; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)