A three-compartment open pharmacokinetic model can explain variable toxicities of cobra venoms and their alpha toxins

• Published in: Toxicon (Oxford) 1996-09, Vol.34 (9), p.1011-1026
• Main Authors: Ismail, M., Aly, M.H.M., Abd-Elsalam, M.A., Morad, A.M.
• Format: Article
• Language: English
• Subjects: Animal poisons toxicology. Antivenoms; Animals; Biological and medical sciences; Biomarkers - blood; Elapid Venoms - administration & dosage; Elapid Venoms - blood; Elapid Venoms - isolation & purification; Elapid Venoms - metabolism; Elapid Venoms - pharmacokinetics; Elapid Venoms - toxicity; Feasibility Studies; Gastric Mucosa - metabolism; Half-Life; Heart - drug effects; Injections, Intravenous; Isotope Labeling; Kidney - drug effects; Kidney - metabolism; Lethal Dose 50; Liver - drug effects; Liver - metabolism; Medical sciences; Models, Theoretical; Myocardium - metabolism; Naja; Rabbits; Species Specificity; Stomach - drug effects; Tissue Distribution; Toxicology
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/0041-0101(96)00055-4

The pharmacokinetic profiles of labelled Naja melanoleuca, Naja nivea, Naja nigricollis and Naja haje venoms and their alpha neurotoxins were determined following rapid i.v. injection into rabbits. The data obtained fitted a triexponential equation characteristic of a three-compartment open pharmacokinetic model comprising a central compartment ‘blood’, a rapidly equilibrating ‘shallow’ tissue compartment and a slowly equilibrating ‘deep’ tissue compartment. The distribution half-lives for the shallow compartment ranged from 3.2 to 5 min, reflecting the rapid uptake of venoms and toxins compared with 22–47 min for the deep tissue compartment denoting much slower uptake. The overall elimination half-lives, t 1 2 β , ranged from 15 to 29 hr, indicating a slow body elimination. Peak tissue concentration was reached within 15–20 min in the shallow tissue compartment. The corresponding values for the deep tissue compartment were 120 min for N. melanoleuca and N. nigricollis venoms and their toxins and 240 min for N. nivea and N. haje venoms and their toxins. Steady-state distribution between the shallow tissue compartment and the blood gave values of 0.50 and 0.92 ( N. melanoleuca), 1.64 and 1.05 ( N. nivea), 0.78 and 0.92 ( N. nigricollis) and 1.70 and 1.03 ( N. haje) for the venoms and their toxins, respectively. The corresponding values for the deep tissue compartment gave ratios of 3.31 and 3.44 ( N. melanoleuca), 2.99 and 1.68 ( N. nivea), 3.74 and 3.79 ( N. nigricollis) and 1.39 and 2.46 ( N. haje) for the venoms and their toxins, respectively. Ratios lower than unity indicate lower venom and toxin concentrations in the tissues than in the blood, while larger ratios denote higher tissue concentrations. The values thus reflect a higher affinity of the venoms and their toxins for the central than the shallow tissue compartment and for the deep tissue than the central compartment. The sites of action of the venoms seem to be located in the deep tissue compartment since most of the pharmacological, biochemical and electrocardiographic effects of the venoms started 30–60 min after i.v. injection. The mean residence time in the body, MRT b, ranged from 20.8 to 51.8 hr, which correlated well with the long duration of the pharmacological and biochemical effects induced by the venoms. The tissue distribution of the venoms and toxins was similar, with the highest uptake being in the kidneys, followed by the stomach, lungs, liver, spleen, intestine, heart and diaphr