Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients.
Amiodarone
Drug-drug interaction
Enantiomer
Stereoselectivity
Tolvaptan
Journal
European journal of clinical pharmacology
ISSN: 1432-1041
Titre abrégé: Eur J Clin Pharmacol
Pays: Germany
ID NLM: 1256165
Informations de publication
Date de publication:
Aug 2022
Aug 2022
Historique:
received:
28
02
2022
accepted:
17
05
2022
pubmed:
24
5
2022
medline:
19
7
2022
entrez:
23
5
2022
Statut:
ppublish
Résumé
The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients. Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism. The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5. This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.
Identifiants
pubmed: 35604424
doi: 10.1007/s00228-022-03341-y
pii: 10.1007/s00228-022-03341-y
doi:
Substances chimiques
Immunosuppressive Agents
0
Tolvaptan
21G72T1950
CYP3A5 protein, human
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Amiodarone
N3RQ532IUT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1311-1320Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP19H00346
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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