Distribution of clozapine in the rat: localization in lung

TH Gardiner, JM Lewis and PA Shore

To determine the distribution of the antipsychotic agent, clozapin (CLZ), a fluorometric procedure for its estimation was devised, and the drug was measured in various tissues of rats after i.p. injection (20 mg/kg). In a 24-hour urine collection, less than 1% injected drug was found. After 1 hour, CLZ concentrations were greatest in lung, spleen, liver and brain (16-64 microgram/g). After 6 hours, CLZ levels in lung remained at 52 microgram/g, whereas concentrations in all other tissues declined to less than 7 microgram/g. When rat lung slices were incubated (O2, 37 degrees C) in CLZ solution (20 microgram/ml), the drug was taken up by the tissue against a concentration gradient, attaining a maximum tissue/medium ratio of 97 after 4 hours. When the concentration of CLZ was raised from 2 to 200 microgram/ml the 1-hour tissue/medium ratio declined from 89 to 21. Chlordiazepoxide, amphetamine and morphine depressed the 1-hour tissue/medium ratio of CLZ by 34 to 50%. CLZ uptake was also decreased 19% by anaerobic conditions and 25% by the presence of 2,4-dinitrophenol. The results suggest that the lung is a site of (active) transport and accumulation for CLZ and perhaps certain other basic drugs.

Volume 206, Issue 1, pp. 151-157, 07/01/1978
Copyright © 1978 by American Society for Pharmacology and Experimental Therapeutics