Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.

Administration, Oral Adult Antidepressive Agents, Second-Generation / administration & dosage Bupropion / administration & dosage Cytochrome P-450 CYP2B6 / genetics Cytochrome P-450 CYP2D6 Inhibitors / administration & dosage Female Humans Male Polymorphism, Single Nucleotide / drug effects Stereoisomerism Tissue Distribution / drug effects

Journal

Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741

Informations de publication

Date de publication:
01 2019
Historique:
received: 16 03 2018
accepted: 08 05 2018
pubmed: 15 5 2018
medline: 16 10 2019
entrez: 15 5 2018
Statut: ppublish

Résumé

Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes.

Identifiants

DOI: 10.1002/cpt.1116 PMID: 29756345 PMC: PMC6927671
pubmed: 29756345
doi: 10.1002/cpt.1116
pmc: PMC6927671
mid: NIHMS968353
doi:

Substances chimiques

Antidepressive Agents, Second-Generation 0
Cytochrome P-450 CYP2D6 Inhibitors 0
Bupropion 01ZG3TPX31
CYP2B6 protein, human EC 1.14.14.1
Cytochrome P-450 CYP2B6 EC 1.14.14.1

Types de publication

Clinical Trial Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

142-152

Subventions

Organisme : FDA HHS
ID : U01 FD004899
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA091842
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000448
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA014211
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States

Informations de copyright

© 2018 American Society for Clinical Pharmacology and Therapeutics.

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Auteurs

Evan D Kharasch (ED)

Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA.
Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri, USA.
Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis, St. Louis, Missouri, USA.

Amanda Crafford (A)

Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA.

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Classifications MeSH

questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Voies d'administration de substances chimiques et des médicaments › Administration par voie orale › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Psychoanaleptiques › Antidépresseurs › Antidépresseurs de seconde génération › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Composés chimiques organiques › Cétones › Propiophénones › Bupropion › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Famille-2 de cytochromes P450 › Cytochrome P-450 CYP2B6 › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des enzymes du cytochrome P-450 › Inhibiteurs du cytochrome P-450 CYP2D6 › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes de chimie organique › Isomérie › Stéréoisomérie › Common Polymorphisms of CYP2B6 Influence...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Pharmacocinétique › Distribution tissulaire › Common Polymorphisms of CYP2B6 Influence...