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Disposition and elimination of BIOLF-143, an antiviral agent, in the rabbit
D J Ecobichon1, F Bondzi-Simpson, A M Comeau
1Department of Pharmacology and Therapeutics, McGill Cancer Centre, Montreal, Canada.
Abstract:
BIOLF-143, (N-(dimethylamino)methylene-9- [[2-hydroxy-1-(hydroxymethyl)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.
Insights
BIOLF-143, an experimental nucleoside, distributes rapidly and is primarily excreted unchanged in urine. This acyclic nucleoside demonstrated no acute toxicity in rabbits, with kidneys appearing as a potential elimination pathway.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- BIOLF-143 is an experimental, purine-based, acyclic nucleoside.
- Understanding its disposition and toxicity is crucial for potential therapeutic applications.
Purpose of the Study:
- To determine the pharmacokinetic disposition of BIOLF-143.
- To investigate the route and rate of excretion.
- To assess biotransformation and acute toxicity.
Main Methods:
- Adult New Zealand rabbits received intravenous (IV) or intraperitoneal (IP) injections of BIOLF-143.
- High-performance liquid chromatography (HPLC) analyzed plasma and tissue concentrations.
- Metabolism and excretion studies were conducted over 48 hours.
Main Results:
- BIOLF-143 exhibited rapid distribution with a dose-dependent plasma half-life of 21-44 minutes.
- The drug was not extensively protein-bound and was recovered in high percentages from plasma (94.4%) and tissues (85-100%).
- The majority (80-87%) was excreted unchanged in urine within 48 hours; no metabolites were detected. No residues were found in feces. No acute toxicity was observed up to 250 mg/kg IP, though kidneys showed high drug levels, suggesting they are an elimination route.
Conclusions:
- BIOLF-143 is rapidly absorbed, distributed, and primarily excreted unchanged via the kidneys.
- The compound demonstrates a favorable pharmacokinetic profile with no observed acute toxicity in rabbits.
- Further investigation into renal handling may be warranted.