Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers.
Administration, Oral
Adult
Aged
Aged, 80 and over
Angiotensin-Converting Enzyme Inhibitors
/ administration & dosage
Blood Pressure
Carboxylic Ester Hydrolases
/ genetics
Female
Healthy Volunteers
Humans
Indoles
/ administration & dosage
Liver
/ enzymology
Male
Middle Aged
Pharmacogenomic Variants
Polymorphism, Single Nucleotide
Prodrugs
/ administration & dosage
Young Adult
Journal
Clinical and translational science
ISSN: 1752-8062
Titre abrégé: Clin Transl Sci
Pays: United States
ID NLM: 101474067
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
18
12
2020
received:
18
07
2020
accepted:
19
12
2020
pubmed:
5
3
2021
medline:
15
2
2022
entrez:
4
3
2021
Statut:
ppublish
Résumé
Trandolapril, an angiotensin-converting enzyme inhibitor prodrug, needs to be activated by carboxylesterase 1 (CES1) in the liver to exert its intended therapeutic effect. A previous in vitro study demonstrated that the CES1 genetic variant G143E (rs71647871) abolished CES1-mediated trandolapril activation in cells transfected with the variant. This study aimed to determine the effect of the G143E variant on trandolapril activation in human livers and the pharmacokinetics (PKs) and pharmacodynamics (PDs) in human subjects. We performed an in vitro incubation study to assess trandolapril activation in human livers (5 G143E heterozygotes and 97 noncarriers) and conducted a single-dose (1 mg) PK and PD study of trandolapril in healthy volunteers (8 G143E heterozygotes and 11 noncarriers). The incubation study revealed that the mean trandolapril activation rate in G143E heterozygous livers was 42% of those not carrying the variant (p = 0.0015). The clinical study showed that, relative to noncarriers, G143E carriers exhibited 20% and 15% decreases, respectively, in the peak concentration (C
Identifiants
pubmed: 33660934
doi: 10.1111/cts.12989
pmc: PMC8301577
doi:
Substances chimiques
Angiotensin-Converting Enzyme Inhibitors
0
Indoles
0
Prodrugs
0
trandolapril
1T0N3G9CRC
Carboxylic Ester Hydrolases
EC 3.1.1.-
CES1 protein, human
EC 3.1.1.1
trandolaprilat
RR6866VL0O
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1380-1389Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL126969
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG048500
Pays : United States
Informations de copyright
© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.
Références
Biochem Pharmacol. 2016 Nov 1;119:76-84
pubmed: 27614009
Pharmacogenomics J. 2016 Jun;16(3):220-30
pubmed: 26076923
Expert Opin Drug Metab Toxicol. 2018 Feb;14(2):131-142
pubmed: 29264996
Lancet. 2010 Mar 13;375(9718):906-15
pubmed: 20226989
J Gerontol A Biol Sci Med Sci. 2014 Apr;69(4):471-8
pubmed: 23873962
Biochem Biophys Res Commun. 2008 May 9;369(3):939-42
pubmed: 18328811
Eur J Clin Pharmacol. 2016 Jun;72(6):681-7
pubmed: 26915813
Am J Cardiol. 2007 Jun 1;99(11):1549-54
pubmed: 17531579
Clin Pharmacol Ther. 2015 Jun;97(6):650-8
pubmed: 25704243
Br J Clin Pharmacol. 2015 Nov;80(5):1131-8
pubmed: 25919042
Drug Metab Dispos. 2009 Sep;37(9):1819-25
pubmed: 19487248
Drugs. 1993;46 Suppl 2:172-81; discussion 182
pubmed: 7512472
Neuropharmacology. 2009 Dec;57(7-8):731-3
pubmed: 19733552
Basic Clin Pharmacol Toxicol. 2016 Dec;119(6):555-561
pubmed: 27228223
Crit Rev Clin Lab Sci. 2018 Jun;55(4):246-263
pubmed: 29663841
Drug Metab Dispos. 2020 Mar;48(3):230-244
pubmed: 31871135
Circulation. 2008 Sep 23;118(13):1383-93
pubmed: 18809808
Pharmacogenet Genomics. 2014 Apr;24(4):204-10
pubmed: 24535487
Br J Clin Pharmacol. 2017 Jul;83(7):1506-1514
pubmed: 28087982
Drug Metab Pharmacokinet. 2006 Jun;21(3):173-85
pubmed: 16858120
Drug Metab Dispos. 2009 Feb;37(2):264-7
pubmed: 19022936
Basic Clin Pharmacol Toxicol. 2017 Dec;121(6):487-492
pubmed: 28639420
Eur J Drug Metab Pharmacokinet. 2016 Aug;41(4):373-84
pubmed: 25864194
N Engl J Med. 2008 May 15;358(20):2148-59
pubmed: 18480207
J Hum Hypertens. 1998 Mar;12(3):189-94
pubmed: 9579769
Drug Metab Dispos. 2016 Apr;44(4):554-9
pubmed: 26817948
Br J Clin Pharmacol. 1993 Feb;35(2):128-35
pubmed: 8443030
J Pharmacol Exp Ther. 2013 Mar;344(3):665-72
pubmed: 23275066
Expert Rev Cardiovasc Ther. 2009 Nov;7(11):1329-40
pubmed: 19900016
Pharmacogenet Genomics. 2008 Oct;18(10):911-20
pubmed: 18794728
Drug Metab Dispos. 2020 Jan;48(1):31-40
pubmed: 31699809
Hypertens Res. 2005 Sep;28(9):719-25
pubmed: 16419644
Hypertension. 1995 Jul;26(1):124-30
pubmed: 7607715
Am Heart J. 2002 Feb;143(2):313-8
pubmed: 11835037
Drug Metab Dispos. 2017 Jun;45(6):666-675
pubmed: 28373266
Med Lett Drugs Ther. 1996 Nov 22;38(988):104-5
pubmed: 8941256
J Am Heart Assoc. 2017 Nov 2;6(11):
pubmed: 29097388
Clin Pharmacol Ther. 2012 Jul;92(1):68-71
pubmed: 22588607
Biochem Pharmacol. 2009 Apr 1;77(7):1266-72
pubmed: 19185566
Drug Metab Dispos. 2017 Nov;45(11):1149-1155
pubmed: 28838926
Mol Pharm. 2019 Feb 4;16(2):632-647
pubmed: 30608694
Am J Hum Genet. 2008 Jun;82(6):1241-8
pubmed: 18485328
Hypertension. 2007 Aug;50(2):299-305
pubmed: 17606861
Eur J Clin Pharmacol. 1991;40(2):149-53
pubmed: 1648489