RT Journal Article
SR Electronic
T1 Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 796
OP 802
DO 10.1124/dmd.110.037614
VO 39
IS 5
A1 Youli Lu
A1 Narisu Bao
A1 Gereltu Borjihan
A1 Yanling Ma
A1 Miaomiao Hu
A1 Chen Yu
A1 Shuijun Li
A1 Jingying Jia
A1 Ding Yang
A1 Yiping Wang
YR 2011
UL http://dmd.aspetjournals.org/content/39/5/796.abstract
AB Ethyl piperate is an effective lipid-lowering drug candidate synthesized from piperine. However, its pharmacokinetic characteristics and oral absorption process remain unclear. A liquid chromatography-tandem mass spectrometry method was applied to determine the oral bioavailability of ethyl piperate. Simulated gastrointestinal pH conditions and intestinal washings were prepared to investigate their contributions to the loss of ethyl piperate. Hydrolysis by carboxylesterase (CES) was evaluated in vitro using microsomes and S9 fractions. In situ intestinal single-pass perfusion experiments were performed to estimate the role of CES in ethyl piperate absorption. The bioavailability of ethyl piperate was extremely low (0.47%) in hamster independent of gastrointestinal environmental effects. Ethyl piperate was a typical substrate of CES with kinetic parameters Km and Vmax of 7.56 ± 1.491 μM and 0.16 ± 0.008 nmol · min−1 · mg protein−1, respectively. CES was responsible for 85.8% of the intestinal hydrolysis of ethyl piperate. Specific inhibition of CES with bis-p-nitrophenyl phosphate (BNPP), decreased degradation clearance to 36% of control with no significant change in absorption clearance. This contrasted with the results of Caco-2 monolayer experiments, which showed a dramatic increase in the apparent permeability coefficient after BNPP treatment. mRNA levels for the CES isozyme, CES2A3, were similar among the three regions of hamster intestine and 60% less than those in liver; CES1B1 mRNA levels were even lower in the intestine and showed a proximal-to-distal decrease. In conclusion, CES markedly contributes to intestinal first-pass hydrolysis of ethyl piperate that is sufficient, but not necessary, to cause the observed extremely low bioavailability.