Comparative Toxicity in Rats and Dogs of Intravenous 1,3-Di(4-Imidazolino-2-Methoxyphenoxy) Propane · Lactate, a Potential Agent for the Treatment of Pneumocystis carinii Pneumonia

Abstract

The subchronic toxicity of DMP · lactate [1,3-di(4-imidazolino-2-methoxyphenoxy)propane · lactate], a new agent with potential for the treatment of the opportunistic infection of Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, was defined in rats and dogs after 28 (rats) or 29 (dogs) daily intravenous doses. Dose levels for both species were 0, 0.5, 2.5 and 4.0 mg/kg/day. Tremors were observed in both rats and dogs at the 2.5 and 4.0 mg/kg doses, while incontinence, anorexia, rhinorrhoea, salivation, convulsions, seizures, moribundity and death occurred in dogs at these doses. All rats survived to the scheduled sacrifice, whereas only 1 male and no female dogs administered 4.0 mg/kg/day survived to day 28 and 1 female at 2.5 mg/kg/ day was moribund on day 27. Languid behaviour was noted in rats and dogs at the highest dose. An alteration in tapetum lucidum reflection was found in dogs dosed at 2.5 and 4.0 mg/kg/day. No haematological or urinalysis indicators of toxicity were seen in either species. Serum alanine amino transferase, aspartate amino transferase and alkaline phosphatase were elevated in dogs at 2.5 and 4.0 mg/kg, while only alkaline phosphatase was increased dose-dependently in rats. No histopathological lesions were found in rats. Periportal inflammation, cytoplasmic vacuolisation of centrilobular hepatocytes and/or hepatocyte hyaline droplet formation were seen in dogs at all doses. Thus, dogs appear to be much more sensitive to DMP toxicity than rats. The differential toxicity response to DMP could be attributed to the different pharmacokinetics in the rat and the dog.