Effects of 24 CYP2D6 variants found in Chinese population on the metabolism of clonidine in vitro.
Chem Biol Interact
; 313: 108840, 2019 Nov 01.
Article
en En
| MEDLINE
| ID: mdl-31585114
BACKGROUND AND OBJECTIVES: Clonidine has been clinically used to treat Tourette's syndrome for decades. There was research finding that clonidine possessed the best risk-benefit ratio, especially for patients associated with attention deficit hyperactivity disorder. CYP2D6 is a significant member of Cytochrome P450 enzymes. The genetic polymorphisms of CYP2D6 greatly affect the clinical effects of drugs even lead to side effects and medical malpractice. Our goal is to research the effect of CYP2D6 genetic polymorphism on the metabolism of clonidine and evaluate the functions of 22 CYP2D6 allelic variants in vitro, which were discovered in Chinese Han population recently. METHODS: This study was carried out through a mature incubation system. The wild-type CYP2D6*1 and 24 variants (CYP2D6*2, CYP2D6*10 and 22 novel CYP2D6 variants) were expressed in insect cells, and the catalytic activity of all the variants were assessed by substrate clonidine. Metabolite 4-OH clonidine was accurately detected via ultra-performance liquid-chromatography tandem mass spectrometry to evaluate the effect of CYP2D6 genetic polymorphism on the clonidine. RESULT: Among the 22 novel CYP2D6 variants, the intrinsic clearance (Vmax/Km) of 21 variants were significantly decreased (from 1.53% to 83.25%) compared to the wild-type. In particular, the following seven variants (CYP2D6* 2, CYP2D6* 10, CYP2D6* 93, CYP2D6* 95, E215K, V327 M and R497C) attract more attention, of which the intrinsic clearance decreased more than 70% compared to the wild-type. Because the variants with significantly reduced intrinsic clearance are more likely to cause adverse reactions than the variants with increased or little changed intrinsic clearance. In addition, the related pharmacokinetic parameters of CYP2D6*92 and CYP2D6*96 could not be acquired for the defect of CYP2D6 nucleotide. CONCLUSION: We comprehensively evaluated the effect of 22 novel CYP2D6 variants on the metabolism of clonidine for the first time and hoped corresponding data provide a reference for metabolism of clonidine for further studies in vivo, and extend our understanding of the clinical drug toxicity or ineffectiveness by CYP2D6 genetic polymorphism.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Clonidina
/
Citocromo P-450 CYP2D6
Límite:
Humans
Idioma:
En
Revista:
Chem Biol Interact
Año:
2019
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Irlanda