Biotransformation of 10-(3-quinuclidinylmethyl)phenothiazine (LM 209), a new anti-allergy agent and the distribution and excretion of its metabolites

Abstract

1. Metabolism of 10-(3-quinuclidinylmethyl)phenothiazine and the distribution and excretion of the metabolites, especially the sulphoxides, were studied in rat and dog after oral and intravenous administration. 2. Urine and bile contained relatively little unchanged drug. The sulphoxide, sulphone, N-oxide and N-oxide sulphoxide derivatives were identified as well as glucuronide and sulphate conjugates, suggesting the formation of hydroxylated products. Faeces contained mainly unchanged drug but also some sulphoxide and N-oxide. In the lung, brain and cerebro spinal fluid only unchanged drug and traces of sulphoxide were found, whereas in liver sulphone and N-oxide were also present. 3. After administration of the 35S-labelled sulphoxide, the distribution of radio-activity was very different from that observed with LM 209. The biological half-life (t0-5) of SM 209 was 3 to 4 times higher than that of the sulphoxide. LM 209 is better absorbed and its diffusion in the organism is superior. 4. Metabolism of LM 209 by liver microsome preparation was more rapid than metabolism of the sulphoxide. 5. These findings indicate that the activity of LM 209 is due more to the molecule itself than to its major metabolite.