Is a diurnal rhythm in bioavailability caused by a rhythm in intestinal absorption?
This study was undertaken to elucidate the influence of diurnal rhythmicity in rats an the intestinal transport step of two model compounds. One of these compounds is a lipophilic drug (griseofulvine) and the other hydrophilic (theophylline). For this purpose, chronically isolated loops in the rat intestine in the proximal ileum were perfused for approximately 24 hours with a solution of theophylline or griseofulvine in phosphate buffered saline. The water flux was also monitored during perfusion. No significant difference between the disappearance rate at day and at night was shown in the perfusion experiments performed, irrespective of the compound under investigation. Only a normal bias in disappearance rate was shown throughout the perfusion experiments. In the waterflux an influx of 2-5 ml/hr was shown; a diurnal rhythm however was completely absent. We conclude therefore that the rhythmicity in plasma levels found in drug disposition experiments are caused by other influential factors, such as difference in food between morning and evening, difference in transit time or gastric emptying or difference in the amount or composition (pH!) of the gastric or intestinal fluid. Based on our experiments, however, these variations are not caused by diurnal variation in the passive transport step in the mucosa.
Tukker
J J
JJ
Department of Pharmaceutics, Faculty of Pharmacy, University of Utrecht, Nederlands.
Meulendijk
A J
AJ
D000818:Animals; D001682:Biological Availability; D001834:Body Water / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D006118:Griseofulvin / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000502:physiology*; D010477:Perfusion; D051381:Rats; D013806:Theophylline / Q000493:pharmacokinetics
D006118:Griseofulvin; D013806:Theophylline