Diurnal exposure profile in rats from dietary administration of a chemical (doxazosin) with a short half-life: interplay of age and diurnal feeding pattern.
Doxazosin, an alpha-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.
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Centre de Recherche, Laboratoires Pfizer, Amboise, France.
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D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics* / Q000633:toxicity; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin; D005247:Feeding Behavior / Q000502:physiology*; D006207:Half-Life; D008297:Male; D011224:Prazosin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D017292:Doxazosin; D011224:Prazosin