ON THE PHARMACOLOGY OF N₁-PARA-CHLOROPHENYL-N₅-ISOPROPYLBIGUANIDE (PALUDRINE)

¹ The Christ Hospital Institute of Medical Research, Cincinnati, Ohio

An investigation of the pharmacological properties of Paludrine has been carried out. This has included: (1) evaluation of acute and chronic toxicities in the mouse, rat, dog, and monkey; (2) investigation of absorption, excretion and tissue localization; (3) explorations of pathways of metabolism. A summary of the results of this study follows.

Wide variations in the acute toxicity of Paludrine for different animal species were noted. The mouse is the most susceptible of the experimental animals included in this study. The dog and monkey are the least susceptible, while the rat occupies an intermediary position. There is an 8 to 20 fold difference between the acute toxicity of Paludrine for the mouse and that for the dog or monkey, the variation depending upon the route of administration.

There are somewhat smaller variations in species susceptibility to the chronic toxicity of Paludrine. The dog appears to be the most susceptible of the test animals; the mouse and monkey are next in order, while the rat is least susceptible.

The symptoms of chronic Paludrine intoxication in all 4 animal species are referrable to an as yet undefined effect of the drug on the gastrointestinal tract. This effect results in almost complete loss of appetite leading to death via starvation. Thus far there has been no evidence of toxic effects of Paludrine on specific organs other than those of the enteric tract. Severe toxemias induced by paludrine are readily reversible when treatment is terminated.

Absorption of Paludrine from the gastrointestinal tract is 70 to 90 per cent complete but is rather slow. The drug is localized in the tissues to a comparatively slight degree. At low intakes there is little difference in the concentrations found in various organs and tissues, other than blood plasma. At higher doses, however, Paludrine accumulates in the liver to a greater extent than in other organs. There is some species difference in the deposition of Paludrine in the tissues, the organs of the dog or monkey containing considerably larger amounts of drug than organs of rats receiving comparable doses. Paludrine disappears from the tissues with extreme rapidity when treatment is terminated.

Only a comparatively small fraction of the Paludrine ingested is eliminated in the urine. Since the drug does not accumulate in the tissues, it has been inferred that it must undergo metabolic alteration. Thus far attempts to elucidate the metabolic fate of Paludrine have yielded negative results.

The pharmacological properties of Paludrine have been compared with those of chloroquine and quinacrine and some of the possible advantages of Paludrine have been indicated.

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