[Absorption, distribution and excretion of (quinuclidinyl-3 methyl)-10-phenothiazine (LM 209), a new antihistamine].
1. The absorption, distribution and elimination of 10-(3-quinuclidinylmethyl)-phenothiazine (LM 209) were studied in the rat and dog after oral or intravenous administration of the 35S-labelled molecule. 2. Determinations of radioactivity in the rat and dog confirmed absorption and showed that the blood levels increase in proportion to the dose but remain very low compared with tissue concentrations. These were highest in the liver and lung and persisted at high level for more than 6 h after dosage. 3. Excretion of radioactivity was by the urinary and faecal routes. The high level of radioactivity in faeces resulted mainly from biliary excretion which was accompanied by much entero-hepatic circulation. 4. The prolonged retention of LM 209, due to binding to blood and tissue proteins and to entero-hepatic circulation, did not lead to noticeable accumulation of the drug after repeated doses. 5. The difference in the intracellular distribution of LM 209 and phenothiazine shows the importance of the quinuclidine N-subsitution on the phenothiazine ring, and results in a greater affinity to sub-cellular particulate fractions (nuclei, mitochondria, microsomes).
[Absorption, distribution and excretion of (quinuclidinyl-3 methyl)-10-phenothiazine (LM 209), a new antihistamine]. 1. The absorption, distribution and elimination of 10-(3-quinuclidinylmethyl)-phenothiazine (LM 209) were studied in the rat and dog after oral or intravenous administration of the 35S-labelled molecule. 2. Determinations of radioactivity in the rat and dog confirmed absorption and showed that the blood levels increase in proportion to the dose but remain very low compared with tissue concentrations. These were highest in the liver and lung and persisted at high level for more than 6 h after dosage. 3. Excretion of radioactivity was by the urinary and faecal routes. The high level of radioactivity in faeces resulted mainly from biliary excretion which was accompanied by much entero-hepatic circulation. 4. The prolonged retention of LM 209, due to binding to blood and tissue proteins and to entero-hepatic circulation, did not lead to noticeable accumulation of the drug after repeated doses. 5. The difference in the intracellular distribution of LM 209 and phenothiazine shows the importance of the quinuclidine N-subsitution on the phenothiazine ring, and results in a greater affinity to sub-cellular particulate fractions (nuclei, mitochondria, microsomes).