Species Differences In Excretion Research Articles

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

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.

SPECIES DIFFERENCES IN EXCRETION PATTERN AND TOXICITY OF SULBENICILLIN

The results of toxicity studies on sulbenicillin (SB-PC) in rats, dogs and monkeys as well as distribution and excretion patterns in these animals and humans were reviewed and, taking into account the results of its clinical trials in 6376 patients, the following conclusion was obtained. 1. There was marked species difference in excretion and distribution of SB-PC. In dogs, unlike other animals including humans, excretion of SB-PC into bile was larger than that into urine, and its distribution in the liver at an extraordinarily high concentration was observed. When SB-PC was intravenously injected to dogs at various dosages, transient but dose-related hepatotoxic signs appeared, and a few animals died at 1500 mg/kg/day. 2. There were no abnormalities in rats treated intramuscularly with 2500 mg/kg/day of SB-PC for 6 months except for a local irritation at the injection site. The excretion pattern of SB-PC in cynomolgus monkeys was quite similar to that in humans, and they tolerated daily intravenous injections at 1500 mg/kg/day for one month well. None of the animals showed any significant changes in hematological, biochemical and histological examinations. 3. In clinical trials of SB-PC, intravenous infusion at 30 g (15 gx 2)/day/man did not affect the normal function of the liver and kidneys in the patients. The above results were compared with those reported for carbenicillin (CB-PC) and it was indicated that SB-PC is less toxic than CB-PC in humans.