PMID- 26558823
OWN - NLM
STAT- MEDLINE
DCOM- 20160913
LR  - 20151209
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 44
IP  - 1
DP  - 2016 Jan
TI  - Human Intestinal Raf Kinase Inhibitor Protein (RKIP) Catalyzes Prasugrel as a 
      Bioactivation Hydrolase.
PG  - 115-23
LID - 10.1124/dmd.115.066290 [doi]
AB  - Prasugrel is a thienopyridine antiplatelet prodrug that undergoes rapid 
      hydrolysis in vivo to a thiolactone metabolite by human carboxylesterase-2 (hCE2) 
      during gastrointestinal absorption. The thiolactone metabolite is further 
      converted to a pharmacologically active metabolite by cytochrome P450 isoforms. 
      The aim of the current study was to elucidate hydrolases other than hCE2 involved 
      in the bioactivation step of prasugrel in human intestine. Using size-exclusion 
      column chromatography of a human small intestinal S9 fraction, another peak 
      besides the hCE2 peak was observed to have prasugrel hydrolyzing activity, and 
      this protein was found to have a molecular weight of about 20 kDa. This prasugrel 
      hydrolyzing protein was successfully purified from a monkey small intestinal 
      cytosolic fraction by successive four-step column chromatography and identified 
      as Raf-1 kinase inhibitor protein (RKIP) by liquid chromatography-tandem mass 
      spectrometry. Second, we evaluated the enzymatic kinetic parameters for prasugrel 
      hydrolysis using recombinant human RKIP and hCE2 and estimated the contributions 
      of these two hydrolyzing enzymes to the prasugrel hydrolysis reaction in human 
      intestine, which were approximately 40% for hRKIP and 60% for hCE2. Moreover, 
      prasugrel hydrolysis was inhibited by anti-hRKIP antibody and 
      carboxylesterase-specific chemical inhibitor (bis p-nitrophenyl phosphate) by 30% 
      and 60%, respectively. In conclusion, another protein capable of hydrolyzing 
      prasugrel to its thiolactone metabolite was identified as RKIP, and this protein 
      may play a significant role with hCE2 in prasugrel bioactivation in human 
      intestine. RKIP is known to have diverse functions in many intracellular 
      signaling cascades, but this is the first report describing RKIP as a hydrolase 
      involved in drug metabolism.
CI  - Copyright (c) 2015 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Kazui, Miho
AU  - Kazui M
AD  - Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), 
      Tokyo, Japan kazui.miho.yk@daiichisankyo.co.jp.
FAU - Ogura, Yuji
AU  - Ogura Y
AD  - Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), 
      Tokyo, Japan.
FAU - Hagihara, Katsunobu
AU  - Hagihara K
AD  - Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), 
      Tokyo, Japan.
FAU - Kubota, Kazuishi
AU  - Kubota K
AD  - Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), 
      Tokyo, Japan.
FAU - Kurihara, Atsushi
AU  - Kurihara A
AD  - Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), 
      Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151111
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (PEBP1 protein, human)
RN  - 0 (Phosphatidylethanolamine Binding Protein)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - EC 3.- (Hydrolases)
RN  - EC 3.1.1.1 (CES2 protein, human)
RN  - EC 3.1.1.1 (Carboxylesterase)
RN  - G89JQ59I13 (Prasugrel Hydrochloride)
SB  - IM
MH  - Activation, Metabolic
MH  - Animals
MH  - Carboxylesterase/antagonists & inhibitors/metabolism
MH  - Catalysis
MH  - Chromatography, Gel
MH  - Chromatography, Liquid
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Humans
MH  - Hydrolases/antagonists & inhibitors/*metabolism
MH  - Hydrolysis
MH  - Intestine, Small/drug effects/*enzymology
MH  - Kinetics
MH  - Macaca fascicularis
MH  - Male
MH  - Models, Biological
MH  - Phosphatidylethanolamine Binding Protein/antagonists & inhibitors/*metabolism
MH  - Platelet Aggregation Inhibitors/*metabolism
MH  - Prasugrel Hydrochloride/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Substrate Specificity
MH  - Tandem Mass Spectrometry
EDAT- 2015/11/13 06:00
MHDA- 2016/09/14 06:00
CRDT- 2015/11/13 06:00
PHST- 2015/07/14 00:00 [received]
PHST- 2015/11/04 00:00 [accepted]
PHST- 2015/11/13 06:00 [entrez]
PHST- 2015/11/13 06:00 [pubmed]
PHST- 2016/09/14 06:00 [medline]
AID - dmd.115.066290 [pii]
AID - 10.1124/dmd.115.066290 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2016 Jan;44(1):115-23. doi: 10.1124/dmd.115.066290. Epub 2015 
      Nov 11.