Destruction of chlorpromazine during absorption by rat intestine in vitro.

Destruction of chlorpromazine during absorption by rat intestine in vitro S. H. CURRY, A. D'MELLo and G. P. MOULD*, Department of Pharnmacology anid Therapeutics, The London Hospital Medical College, Turner Street, Londonl E.1 It is commonly supposed that orally administered chlorpromazine is rapidly and well absorbed in man, although there appears to have been no systematic investigation of the absorption phenomenon (Goodman & Gilman, 1965; Shepherd, Lader & Rodnight, 1968). Doubt was recently cast on the supposition by measurements of unchanged chlorpromazine in plasma of man and animals (Curry, Davis, Janowsky & Marshall, 1970; Hollister, Curry, Derr & Kanter, 1970; Curry, Derr, Maling & Williams, 1970); concentrations of unchanged drug in plasma after injected doses were 3-10 times higher than those after oral doses during the 48 h following administration. This indicated incomplete absorption of oral doses as unchanged drug. In contrast, concentrations of metabolites of chlorpromazine in urine after doses by the two routes were similar. This indicated complete absorption, either as unchanged drug as or metabolites. We therefore investigated the possibility that the drug could be converted to absorbable metabolites during the process of absorption. Krebs bicarbonate fluid containing 35S-chlorpromazine (50, 100 and 200 ug/ml) was circulated at 370 C through the lumen of rat isolated intestine. The serosal surface was bathed with a similar solution containing no chlorpromazine (technique of Fisher & Parsons, 1949). Unchanged chlorpromazine, measured by gas chromatography, disappeared rapidly from the luminal solution and was partially transferred to the serosal solution and partially retained in the intestinal wall. Concentrations of total radioactivity and of unchanged chlorpromazine were similar both in the luminal solution and in the intestinal wall. In contrast, radioactivity appeared in the serosal solution more rapidly than did unchanged chlorpromazine; at the end of the experiment (60 min), 15-32% of the serosal radioactivity was present as unchanged drug. These observations indicated that chlorpromazine was decomposed during absorption in vitro. The mechani sm of this decomposition is not clear, but results of control experiments demonstrated that chemical decomposition unrelated to the presence of intestinal material did not occur. Biochemical decomposition may have been brought about by intestinal flora or enzymes in the intestinal wall. If this process were to occur in vivo it might be the cause of concentrations of unchanged drtug in plasma being less after oral doses than after injected doses.