Assessment of drug exposure in rat dietary studies

Abstract

1. The objective of this study was to justify the evaluation of exposure of animals to chemical substances on the basis of only three blood samples taken during a 24-h period, but still with acceptable accuracy.

2. Fischer rats were fed a diet mixed with either paracetamol, 100mg.kg^-1 (short half-life compound), antipyrine, 100mg.kg^-1 (medium half-life compound), or phenylbutazone, 50mg kg^-1 (long half-life compound) for 3 weeks. It had been shown in a preliminary study that these compounds when administered at these dose levels did not influence feeding behaviour. At the end of 3 weeks, five rats were sampled every 3 h beginning and ending at 19.00 h (45 rats in total) and plasma concentrations were measured using h.p.l.c.

3. The area under the curve over 24h (AUC₂₄), calculated using all nine concentrations was considered to be the true AUC₂₄. Subsequently, estimates of this parameter were made using different combinations of concentrations at three or even two selected time points.

4. For each compound, the highest concentration occurred at 07.00 h. It was shown that using the concentrations at 07.00, 10.00 and 16.00 h the estimate of the AUC₂₄ was within 15% of the true value.

5. In comparison with a gavage study in the same rat (strain and age), bioavailability was lower in the diet study with relative bioavailabilities of 27, 22 and 61% for paracetamol, antipyrine and phenylbutazone, respectively.

6. In conclusion, drug exposure as expressed by AUC₂₄ and C_max can be accurately determined in rat studies using compound administration in the diet by measuring concentrations at three selected time points for compounds with elimination half-lives ranging from about 1 to 5 h.