Comparative pharmacokinetics of dimethoate poisoning in the minipig and human
Anderson JM (1,2,3) Petersson K (3) Friberg LE (3) Eddleston M (1,4) Clutton RE (5) Worek F (6), Thiermann H (6), Buckley NA (1,2).
1. South Asian Clinical Toxicology Research Collaboration, Sri Lanka 2. University of New South Wales; 3. Department of Pharmaceutical Biosciences, Uppsala University 4. Clinical Pharmacology Unit and 5. Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK, 6. Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
Objectives: Organophosphorus pesticide (OP) poisoning is a major clinical problem in rural Asia. In contrast to other class II OPs, dimethoate is more toxic and most deaths result from refractory hypotension 12-36 hours after exposure. A pig model was developed to explore the pathophysiology of this poisoning. We wished to establish if pharmacokinetic and toxicity profiles in this model are similar to acute human poisonings. For this purpose, a population PK model was developed for pigs to compare with data from humans
Methods: Six Gottingen minipigs (Weight: 16-26kg) were dosed with dimethoate at 1g/kg (3 pigs), 0.5g/kg (2), or 0.33g/kg (1). Serial plasma samples were collected hourly for 13 hrs (when they were euthanized) or until death. In addition, acute poisoning data was collected from patients (n=62; female=4; age 15-68; samples 1-11 per patient) where the volume ingested was unrealisable in most cases. Dimethoate, omethoate, RBC-AChE and BuChE were measured at each time point for pigs and humans. PK models for dimethoate in pigs and humans were developed using NONMEM 7.
Results: A one compartment PK model with absorption described as a combination of zero (~25%) and first order (~75%) kinetics best described the pig data. There was a large volume of distribution: Vd/F = 319 L, 0.3% CV. Elimination was rapid and non-linear with Vmax = 37 ng/h, 27% CV; Km = 440 mM (IIV not significant). The full PK model comparison with human acute poisoning data is in development; however, preliminary findings suggest a dimethoate kinetic profile similar to that in minipigs considering shape and duration. The pig model indicates a plasma half-life of ~6hrs. Calculations from acute poisoning data in humans indicated a plasma half-life ~6-8 hrs (Eyer, unpublished). The large Vd/F is unexpected given the low lipid solubility of dimethoate (log Po/w=0.7), but indicates widespread tissue binding and/or a low bioavailability. Interestingly, bioavailability appeared to decrease as dose increased.
Conclusions: Our preliminary PK findings support the further use of this toxicological minipig model to examine delayed sub-acute clinical outcomes such as respiratory failure and hypotension. The human PK, metabolite and PD models for pigs and humans are in development