Dietary induced obesity and changes in the biodistribution and metabolism of amiodarone in the rat.
J Pharm Sci. 2018 Jul 12;:
Authors: Abdussalam A, Al-Agili M, Al Nebaihi HM, Mayo PR, Gabr RQ, Brocks DR
The metabolism and biodistribution of the antiarrhythmic drug amiodarone was assessed in male Sprague-Dawley rats given either normal chow or high fat and/or high fructose diets for 14 weeks. After the feeding period, microsomes were prepared from liver and intestine and the metabolism of amiodarone to desethylamiodarone was determined. Intrinsic clearance was reduced by hepatic microsomes isolated from rats given high calorie diets. In intestinal microsomes there was no change or a small increase in metabolic rate in obese rats. A biodistribution study was also undertaken in a group of Control and high fat+high fructose-fed rats. Excess calories led to a significant increase in plasma amiodarone compared to normal chow-fed Control animals. A population pharmacokinetic analysis of amiodarone confirmed that its oral clearance was reduced. In plasma there was a decrease in the metabolite to drug ratio. Some tissue:plasma ratios of amiodarone in high calorie-fed rats were aligned with a decrease in plasma unbound fraction. It is concluded that the findings reinforced those of a recent report where we found decreases in expressions of enzymes involved in amiodarone dealkylation, in showing greater exposure and lower oral clearance, and generally decreases in liver microsomal metabolism of amiodarone after high calorie diets.
PMID: 30017888 [PubMed – as supplied by publisher]