The Mode of Action of Phenothiazine as an Anthelmintic. The Uptake of 35S-Labelled Phenothiazine by the Tissues of Nematode Parasites and Their Hosts

Abstract

Ascaridia galli, Nippostrongylus muris, and Haemonchus contortus took up phenothiazine in vitro at the rate of 0.12, 0.18, and 0.26 mg./g. dry wt./hour. The uptake, which was fastest at pH 6.0, was increased in the presence of a wetting agent. It was not proportional to the relative surface area/wet weight of the parasites. The ligaturing of A. galli did not appreciably reduce uptake of the drug in vitro. In vivo, the uptake of phenothiazine by N. muris and A. galli was about 5 times as fast as in vitro. In both parasites the drug reached a level of about 1 mg./g. dry wt. 60 min. after dosing. Thereafter, the phenothiazine content rose steadily to a level of about 1.5-2.5 mg./g. dry wt. which was maintained for several hours. The uptake of the drug by the parasites was 5-10 times greater than that of the mucosa of the small intestine of host animals. The blood, liver, and muscle of host animals also took up the drug in much smaller amounts than did the parasites. When A. galli was exposed to phenothiazine in vitro and in vivo, the concn. of the drug was found in descending order in the tissues of the intestine, the reproductive system, and muscle. The amounts of phenothiazine found in A. galli expelled from the host by the action of the drug varied from 1.6 to 3.3 mg./g. dry wt.; parasites that survived treatment contained 1.1-2.1 mg./g. dry wt. Though the phenothiazine content of N. muris sometimes rose above 2.5 mg./g. dry wt. this parasite was not obviously affected by the drug. Both A. galli and N. muris exposed to phenothiazine in vivo retained a large proportion of the drug in their tissues when they were incubated in phenothiazine-free saline in vitro. It is suggested that phenothiazine enters nematode parasites largely through the cuticle. The relatively small uptake of the drug by host animals as compared to their parasites may account for the differential toxicity to host and parasite. Failure of phenothiazine to "poison" N. muris may be due to lack of dependence on energy from anerobic sources. The necessity for the relatively large doses of phenothiazine needed for anthelmintic treatment is discussed.