PMID- 32653591
OWN - NLM
STAT- MEDLINE
DCOM- 20201231
LR  - 20201231
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 180
DP  - 2020 Oct
TI  - Type 2 diabetes mellitus decreases systemic exposure of clopidogrel active 
      metabolite through upregulation of P-glycoprotein in rats.
PG  - 114142
LID - S0006-2952(20)30378-6 [pii]
LID - 10.1016/j.bcp.2020.114142 [doi]
AB  - Patients with diabetic mellitus tend to have a poor response to clopidogrel 
      (Clop) due to reduced generation of active metabolite (Clop-AM). However, the 
      underlying mechanism is not elucidated. A type 2 diabetic mellitus (T2DM) rat 
      model was established by combining high-fat diet feeding and low-dose 
      streptozotocin (STZ) injection. The reduced Clop-AM exposure was observed in T2DM 
      rats after oral administration of Clop. However, in vitro liver microsomes 
      incubated with Clop exhibited increased Clop-AM levels in T2DM rats due to a 
      significant decrease in carboxylesterase (CES)1 expression and activity and a 
      significant increase in the expression or activity of CYP1A2 and CYP3A. 
      Interestingly, different from oral administration, the significantly increased 
      C(max) of Clop-AM was observed in T2DM rats after intravenous injection, with no 
      difference in AUC(0-t) and t(1/2) values between the two strains. Meanwhile, in 
      situ single -pass intestinal perfusion study showed lower absorption rate 
      constant (Ka) and effective apparent permeability values (P(eff)) of Clop in T2DM 
      rats than in control rats. It is explained by the increased expression or 
      function of P-glycoprotein (P-gp) and pregnane X receptor (PXR) in duodenum and 
      jejunum of T2DM rats. Moreover, the decreased Clop-AM level in T2DM rats was 
      eliminated by the pretreatment of cyclosporin A, a P-gp inhibitor. It suggests 
      that intestinal absorption, not hepatic metabolism is responsible for the reduced 
      Clop-AM exposure in T2DM rats. P-gp might be the key factor causing the reduction 
      of Clop absorption, consequently making less Clop available for Clop-AM 
      formation.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Yao, Hongwei
AU  - Yao H
AD  - School of Life Sciences, Jilin University, Changchun, China.
FAU - Gu, Jingkai
AU  - Gu J
AD  - Research Center for Drug Metabolism, School of Life Science, Jilin University, 
      Changchun, China.
FAU - Shan, Yuqin
AU  - Shan Y
AD  - Research Center for Drug Metabolism, School of Life Science, Jilin University, 
      Changchun, China.
FAU - Wang, Yani
AU  - Wang Y
AD  - School of Life Sciences, Jilin University, Changchun, China.
FAU - Chen, Xue
AU  - Chen X
AD  - School of Life Sciences, Jilin University, Changchun, China.
FAU - Sun, Dong
AU  - Sun D
AD  - Research Center for Drug Metabolism, School of Life Science, Jilin University, 
      Changchun, China; Key Laboratory of Molecular Pharmacology and Drug Evaluation, 
      Ministry of Education, Yantai University, Yantai, China.
FAU - Guo, Yingjie
AU  - Guo Y
AD  - School of Life Sciences, Jilin University, Changchun, China. Electronic address: 
      guoyingjie@jlu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200710
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - A74586SNO7 (Clopidogrel)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*biosynthesis
MH  - Animals
MH  - Clopidogrel/*administration & dosage/*metabolism
MH  - Diabetes Mellitus, Experimental/*blood/diet therapy
MH  - Diabetes Mellitus, Type 2/*blood/drug therapy
MH  - Diet, High-Fat/adverse effects
MH  - Intestinal Absorption/drug effects/physiology
MH  - Male
MH  - Microsomes, Liver/drug effects/metabolism
MH  - Platelet Aggregation Inhibitors/administration & dosage/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Up-Regulation/drug effects/*physiology
OTO - NOTNLM
OT  - Active metabolites
OT  - Clopidogrel
OT  - P-glycoprotein
OT  - Pharmacokinetics
OT  - Type 2 diabetes mellitus
EDAT- 2020/07/13 06:00
MHDA- 2021/01/01 06:00
CRDT- 2020/07/13 06:00
PHST- 2020/05/19 00:00 [received]
PHST- 2020/07/05 00:00 [revised]
PHST- 2020/07/07 00:00 [accepted]
PHST- 2020/07/13 06:00 [pubmed]
PHST- 2021/01/01 06:00 [medline]
PHST- 2020/07/13 06:00 [entrez]
AID - S0006-2952(20)30378-6 [pii]
AID - 10.1016/j.bcp.2020.114142 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2020 Oct;180:114142. doi: 10.1016/j.bcp.2020.114142. Epub 2020 
      Jul 10.