title: In vitro and in vivo trans-esterification of 1-[2(R)-(2-amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]-3(S)-benzyl-piperidine-3-carboxylic acid ethyl ester and the effects of ethanol on its pharmacokinetics in rats.
abstract: OBJECTIVE
  To investigate the in vitro trans-esterification of 1-[2(R)-(2-amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]-3(S)-benzyl-piperidine-3-carboxylic acid ethyl ester (compound A) and to determine the effects of ethanol on its in vivo pharmacokinetics in male Sprague-Dawley rats.
  
  
  METHODS
  The effects of deuterated [d5]ethanol on the hydrolysis and trans-esterification of compound A in rat plasma and rat liver microsomes in the presence or absence of bis(p-nitrophenyl) phosphate (BNPP), a carboxylesterase inhibitor, were investigated. Following an oral pretreatment with deuterated ethanol in conjunction with an intravenous dose of compound A to rats, the pharmacokinetics of compound A and deuterated compound A were evaluated.
  
  
  RESULTS
  It was observed that the amount of deuterated compound A generated increased with increasing amounts of deuterated ethanol in incubates, whereas the amount of hydrolyzed product (compound B) decreased. BNPP inhibited both the hydrolysis and the trans-esterification of compound A. Furthermore, the pharmacokinetics of compound A in rats receiving ethanol was altered, such that the plasma clearance decreased by 1.5-fold and the elimination rate constant decreased by 2-fold. Deuterated compound A was determined, confirming that trans-esterification proceeded in vivo; approximately one third of the intravenous dose of compound A underwent trans-esterification.
  
  
  CONCLUSIONS
  In the presence of ethanol, compound A underwent trans-esterification catalyzed by carboxylesterases. Ethanol pretreatment resulted in a decrease in the in vivo clearance of compound A mainly due to trans-esterification with ethanol.
authors.affiliation: Department of Basic Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. zhesheng_chen@merck.com
authors.forename: Zhesheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Arun K
authors.initials: AK
authors.lastname: Agrawal
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Franklin
authors.forename: Kwan H
authors.initials: KH
authors.lastname: Leung
authors.forename: Shuet-Hing Lee
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D003903:Deuterium; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D004951:Esterification / Q000187:drug effects*; D004952:Esters / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019382:Human Growth Hormone / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002264:Carboxylic Acids; D004952:Esters; C113159:L 163540; D009596:Nitrophenols; D010880:Piperidines; D019382:Human Growth Hormone; D000431:Ethanol; C002887:bis(4-nitrophenyl)phosphate; D003903:Deuterium; D002265:Carboxylic Ester Hydrolases