Diurnal exposure profile in rats from dietary administration of a chemical (doxazosin) with a short half-life: Interplay of age and diurnal feeding pattern
✍ Scribed by C. Charuel; P. Comby; A. M. Monro
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- English
- Weight
- 471 KB
- Volume
- 12
- Category
- Article
- ISSN
- 0260-437X
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✦ Synopsis
Doxazosin, an a-adrenergic blocking agent, has a plasma half-life in male rats of 1-2 h after i.v. administration. Plasma concentrations of doxazosin were measured in male rats receiving the drug mixed in the diet at dose levels from 5 to 40 mg kg-I. Samples taken at 4-h intervals during the light (0700-1900) and dark phases revealed peak concentrations at 0400 which were only about three times higher than the trough concentrations observed ca. 12 h later. The 24-h area under the curve (AUC) values increased disproportionately with dose and with age from 2 months up to 8 months of age; thereafter they were fairly stable to 24 months of age. This age-related effect may have been due to a reduction in clearance andlor a change in the feeding pattern of the rats. Young rats consumed ca. 84% and old rats only 45% of their daily feed during the nocturnal (active) phase. Given the known diurnal rhythms in absorption, protein binding and enzyme metabolising activity, such a change in feeding pattern with age may have wider toxicokinetic implications.