Pharmacokinetics and metabolism of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine) in rat, mouse, dog and man

The absorption, distribution, metabolism and excretion of 2-chloro-11-(2-dimethylaminoethoxy)dibenzo [b,f]thiepine (zotepine), a new neuroleptic agent, were investigated in rat, mouse, dog and man. Zotepine was absorbed rapidly and almost completely from the gastrointestinal tract in all species after oral dosing. The serum level of the unchanged drug in man was comparatively higher than in animals. The serum half-lives of zotepine after i.v. dosing were approximately 3.2 h in rats, 1.5 h in mice and 3.0 h in dogs. The drug and radioactive metabolites were rapidly distributed to the tissues of rats and mice, and the brain levels of the unchanged drug were about 20 to 30 times higher than the serum levels. Only small amounts of the unchanged drug were excreted in the urine in all species; faecal excretion through the bile was the main route of elimination of the drug and metabolites. Extensive biliary excretion and enterohepatic circulation of the radioactive compound were observed in rats. Zotepine was well metabolized in the body. Besides N-demethylation and oxygenation of the N and/or S atoms, hydroxylation of the aromatic ring and consecutive conjugation were important metabolic pathways of zotepine.