Noninvasive determination of acetaminophen disposition in Down's syndrome.
In this study we evaluated subjects with Down's syndrome for the possibility that direct or indirect gene dosage effects of trisomy 21 alter the fate of acetaminophen. We also investigated the usefulness of noninvasive sampling techniques to obtain parameter estimates for drug disposition in these developmentally disabled individuals. After administration of 5 mg/kg and 20 mg/kg oral doses of acetaminophen, subjects with Down's syndrome resembled control subjects in most pharmacokinetic and metabolic parameters, including apparent half-life, volume of distribution per kilogram body mass, total body clearance per kilogram of body mass, extrapolated saliva concentration at time zero, and the urinary excretion of acetaminophen glucuronide and sulfate conjugates. Glutathione conjugation tended to increase and sulfate conjugation tended to decrease in all subjects as the acetaminophen dose increased from 5 mg/kg to 20 mg/kg. Results based on these samples of very limited size also suggest that acetaminophen metabolism to glutathione-derived conjugates may have been increased in subjects with Down's syndrome. The similarity of estimates of acetaminophen pharmacokinetics and data on metabolic fate between subjects with Down's syndrome and normal volunteers indicates that large effects of trisomy 21 on these processes are unlikely. Also, these results were in agreement with extensive data obtained with invasive techniques, indicating that simple noninvasive methodologies appear to be well suited for studying acetaminophen disposition in populations of developmentally disabled individuals.