The impact of experimental hyperlipidemia on the distribution and metabolism of amiodarone in rat.
The tissue distribution and hepatic microsomal metabolism of amiodarone were studied in a hyperlipidemic rat model. Rats were rendered hyperlipidemic by the intraperitoneal injection of poloxamer 407. Other normolipidemic animals given saline in place of poloxamer 407 were used as control animals. After single intravenous injection of amiodarone HCl (25mg/kg) rats were anesthetized and plasma and tissue specimens were obtained. Liver microsomal protein was harvested and used to measure velocity of desethylamiodarone formation from amiodarone and cytochrome P450 (CYP) protein expression. Hyperlipidemia caused large increases in plasma concentrations of amiodarone. In tissues, however, concentrations of drug selectively increased, decreased or did not change. In heart, the site of action of the drug, as well as liver and spleen, amiodarone concentrations increased. In other tissues such as kidney, lung and brain, concentrations decreased. No changes were seen in fat or thyroid. Decreases were observed in liver metabolic efficiency, and expression of CYP3A1/2 and 2C11. No changes were seen in CYP2B1/2, 2C6, 2D1 or 1A2. This experimental hyperlipidemia caused a complex pattern of changes in tissue distribution of AM. In addition, there are decreases in the expression of some important rat CYP isoenzymes.
Shayeganpour
Anooshirvan
A
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Korashy
Hesham
H
Patel
Jigar P
JP
El-Kadi
Ayman O S
AO
Brocks
Dion R
DR
D000638:Amiodarone / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006949:Hyperlipidemias / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D020442:Poloxamer; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000889:Anti-Arrhythmia Agents; D020442:Poloxamer; D003577:Cytochrome P-450 Enzyme System; C036116:desethylamiodarone; D000638:Amiodarone