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© 1990 Oxford University Press

other

Disposition and Elimination of BIOLF-143, an Antiviral Agent, in the Rabbit

D. J. ECOBICHON*, F. BONDZI-SlMPSON*, A. M. COMEAU*, K. M. MEKHAEL{dagger}, P. MAJOR{ddagger} and K. K. OGILVIE{dagger}

*Department of Pharmacology and Therapeutics, McGill University Montreal, Canada H3G IY6 {dagger}Department of Chemistry, McGill University Montreal, Canada H3G IY6 {ddagger}McGill Cancer Centre, McGill University Montreal, Canada H3G IY6

Received March 15, 1989; accepted June 27, 1989

Disposition and Elimination of BIOLF-143, an Antiviral Agent, in the Rabbit. ECOBICHON, D. J., BONDZI-SIMPSON, F., COMEAU, A. M., MEKHAEL, K. M., MAJOR, P., AND OGJLVIE, K. K. (1990). Fundam. Appl. Toxicol. 14, 160–166. BIOLF-143, (N-(dimethylamino)methy-lene-9-[[2-hydroxy-l-(hydroxyrnethyl)ethoxy]methyl]guanine), an experimental, purine-based, acyclic nucleoside was administered by iv or ip injection to adult, male and female, albino New Zealand rabbits in order to determine: (1) the pharmacokinetic disposition, (2) the route and rate of excretion, (3) the biotransformation, and (4) the acute toxicity of the agent. HPLC analysis of blood plasma concentrations of BIOLF-143 was conducted following iv injections of 50 or 100 mg/kg and ip injections of 250 mg/kg. Tissue levels of BIOLF-143 were analyzed at 60 min following an ip injection of 100 mg/kg. Metabolism/excretion studies were conducted over a 48-hr period following ip injections of BIOLF-143 (100 mg/kg). The nucleoside was rapidly distributed in the body, with the dose-dependent, estimated plasma half-life being 21–44 min. The drug molecule was not extensively bound to proteins, being quantitatively recovered from plasma (94.4 ± 3.2%) and a variety of tissues (85–100%). The bulk of the drug (80–87%) was recovered in the urine within 48 hr of treatment, with no metabolites or unique, unidentifiable peaks being detected in HPLC chromatograms. No drug residue was found in feces. No overt toxicity or untoward signs of latent toxicity were observed in animals receiving acute doses of BIOLF-143 up to 250 mg/kg ip. A potential target organ might be the kidney since high levels of drug residue were detected 60 min post-treatment and this appeared to be the route of elimination from the body.


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