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Diurnal exposure profile in rats from dietary administration of a chemical (doxazosin) with a short half‐life: Interplay of age and diurnal feeding pattern
Author(s) -
Charuel C.,
Comby P.,
Monro A. M.
Publication year - 1992
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2550120104
Subject(s) - circadian rhythm , endocrinology , nocturnal , medicine , toxicokinetics , doxazosin , diurnal temperature variation , chemistry , adult male , half life , zoology , pharmacokinetics , biology , metabolism , blood pressure , atmospheric sciences , geology
Doxazosin, an α‐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 −1 . 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 and/or 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.