The chlorophenoxy herbicide MCPA: A mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs.

Abstract

1. Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50-67% dose in rat, ∼40% in human and 2-27% in dog. No dog specific metabolite is apparent. 2. In rat and human, MCPA and metabolites are rapidly eliminated in urine (65-70% within 24 hours) but in dog, excretion is via urine and faeces (20-30% within 24 hours), with renal excretion saturating between 5 and 100 mg.kg bw. 3. The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15-17 hour) but higher in dog (47 hour). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing. 4. The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new in vitro flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog.