Hypolipidaemic drugs are activated to acyl-CoA esters in isolated rat hepatocytes. Detection of drug activation by human liver homogenates and by human platelets.
The formation of acyl-CoA esters of the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate and nafenopin was studied in isolated rat hepatocytes. The concentration of ciprofibroyl-CoA in the liver of ciprofibrate-treated rats was in the range of 10-30 microM. The three drugs formed acyl-CoA esters when incubated with isolated hepatocytes. Their formation was saturable and reached a plateau after 30 min incubation. Maximal intracellular concentrations of ciprofibroyl-CoA and clofibroyl-CoA (100 microM and 55 microM respectively) were attained at 0.5 mM of the free drugs in the incubation medium, whereas for nafenopin-CoA, the maximal intracellular concentration (9 microM) was reached at 1 mM-nafenopin. At low concentrations of the hypolipidaemic compounds in the incubation medium a significant proportion of the total intracellular drug was present as its acyl-CoA ester (25-35% for ciprofibrate). When isolated hepatocytes were incubated with a ciprofibrate concentration comparable with that observed in the blood of drug-treated rats (0.1 mM), ciprofibroyl-CoA attained an intracellular concentration similar to that previously observed in the liver of treated rats. The formation of ciprofibroyl-CoA by isolated rat hepatocytes was stimulated by the addition of carnitine and partially inhibited by the addition of palmitate. Further, it was shown that human liver homogenates synthesized ciprofibroyl-CoA at a rate similar to that observed for rat liver homogenates. Solubilized human platelets also formed ciprofibroyl-CoA, although at a rate two orders of magnitude lower than that of liver. The results support the view that acyl-CoA esters of hypolipidaemic peroxisome proliferators may be the pharmacologically active species of the drugs.
Bronfman
M
M
Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago.
Morales
M N
MN
Amigo
L
L
Orellana
A
A
Nuñez
L
L
Cárdenas
L
L
Hidalgo
P C
PC
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D001792:Blood Platelets / Q000378:metabolism*; D002331:Carnitine / Q000494:pharmacology; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D058607:Fibric Acids; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D009255:Nafenopin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D017830:Octoxynol; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000214:Acyl Coenzyme A; D058607:Fibric Acids; D008055:Lipids; D010169:Palmitic Acids; D009255:Nafenopin; C051514:ciprofibrate-coenzyme A; C051515:nafenopin-coenzyme A; D019308:Palmitic Acid; D011092:Polyethylene Glycols; D002995:Clofibric Acid; D017830:Octoxynol; C019304:ciprofibrate; D002331:Carnitine