In vitro evaluation of inhibitory effects of antidiabetic and antihyperlipidemic drugs on human carboxylesterase activities.
Human carboxylesterase (CES) 1A is responsible for the biotransformation of angiotensin-converting enzyme (ACE) inhibitors such as imidapril and temocapril. Because antidiabetic or antihyperlipidemic drugs are often coadministered with ACE inhibitors in clinical pharmacotherapy, the inhibitory effect of these drugs on CES1A1 enzyme activity was investigated. In addition, the inhibitory effect on CES2 enzyme activity was evaluated to compare it with that on CES1A1. The inhibitory effects were evaluated with 11 antidiabetic and 12 antihyperlipidemic drugs. The imidapril hydrolase activity by recombinant CES1A1 was substantially inhibited by lactone ring-containing statins such as simvastatin and lovastatin and thiazolidinediones such as troglitazone and rosiglitazone. The activity in human liver microsomes was also strongly inhibited by simvastatin and troglitazone (K(i) = 0.8 ± 0.1 and 5.6 ± 0.2 μM, respectively). However, statins containing no lactone ring such as pravastatin and fluvastatin did not show strong inhibition. 7-Ethyl-10-[4-(1-piperidono)-1-piperidono]carbonyloxycamptothecin hydrolase activity by recombinant human CES2 was substantially inhibited by fenofibrate (K(i) = 0.04 ± 0.01 μM) as well as by simvastatin (0.67 ± 0.09 μM). Other fibrates such as clinofibrate and bezafibrate did not show strong inhibition. Thus, the inhibitory effects of the thiazolidinediones and fenofibrate on CES1A1 and CES2 were different. Some statins such as simvastatin and lovastatin, thiazolidinediones, and fenofibrate might attenuate the drug efficacy of prodrugs biotransformed by CES1A and CES2.
Fukami
Tatsuki
T
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Takahashi
Shiori
S
Nakagawa
Nao
N
Maruichi
Taiga
T
Nakajima
Miki
M
Yokoi
Tsuyoshi
T
D000818:Animals; D043182:Carboxylesterase / Q000037:antagonists & inhibitors*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology; D018411:Spodoptera
D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; C072888:CPT-11 converting enzyme; C517204:CES2 protein, human; C474609:CES1 protein, human