CYP2D6*10 polymorphism and the enantioselective O‐desmethylation of S‐(+)‐ and R‐(‐)‐venlafaxine in Japanese psychiatric patients

Abstract

According to previous studies, R‐(‐)‐venlafaxine (VEN) has higher enantioselectivity than S‐(+)‐VEN, and the plasma concentration of R‐(‐)‐VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady‐state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O‐desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S‐(+)‐VEN were approximately 1.9‐fold higher than those of R‐(‐)‐VEN. The plasma concentrations of S‐(+)‐VEN and R‐(‐)‐VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S‐(+)‐VEN and R‐(‐)‐VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R‐(‐)‐ODV/R‐(‐)‐VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R‐(‐)‐VEN and S‐(+)‐VEN. Further studies are needed to examine how these findings affect clinical practice.

Role of JNK in the Regulation of Xenobiotic Metabolizing Function of Hepatocytes

“…The discovered properties of the JNK inhibitor can be used to develop a fundamentally new approach to personification and increase the effectiveness of venlafaxine antidepressant therapy [7,8]. Based on the identified phenomena, JNK inactivation in liver cells can increase the level of drug transformation in low metabolizers (persons with low CYP2D6 expression, or in patients with liver diseases [3,4,6]) to the normal level (i.e. in extensive metabolizers of venlafaxine).…”

“…In 30 min, the venlafaxine (Aarti Industries) was added to the homogenate in a dose of 100 ng/ml and the cell suspension was incubated at 37°C in a TS-100 thermoshaker (Biosan). In 30 min, 1, 2, and 4 h, the content of the main venlafaxine metabolite O-desmethylvenlafaxine (O-DVLF) was evaluated [6,7]. The control was liver homogenate containing equivalent amounts of venlafaxine and solvent (DMSO, final concentration of 0.15%).…”

“…This psychotropic pharmaceutical (presented by a racemate of R-and S-enantiomers) is one of the most effective modern antidepressants; its therapeutic effect is realized via blockade of serotonin, norepinephrine, and dopamine reuptake [9]. However, its low efficiency in some cases [3,5,6] requires the development of personalized approaches to venlafaxine therapy, including modification of its pharmacokinetics and pharmacodynamics [1].…”

A Bibliometric and Visual Analysis of Single Nucleotide Polymorphism Studies in Depression

“…CYP2D6 is involved in the metabolism of 5-HT in the brain, which is linked to psychiatric disorders, as well as the synthesis of serotonin and dopamine [ 90 ]. Among these alleles, *10 is a mutation with a high allele frequency in Asian populations [ 91 ]. A study on patients with recurrent depression found that an SNP in CYP2D6 was associated with the efficacy of the antidepressant duloxetine [ 92 ].…”

C-Jun N-Terminal Kinases Inhibition: A New Approach to the Regulation of Venlafaxine Pharmacokinetics

“…However, the specific roles of individual signal transduction pathways in regulating the xenobioticmetabolizing function of cells competent in this regard are largely unknown. Simultaneously, uncovering the involvement and distinct roles of particular signaling molecules in the biotransformation of pharmacologically active substances can form the basis for the development of innovative approaches to personalized pharmacotherapy [7][8][9][10][11]. Therefore, it is pertinent to investigate the potential for controlling the intensity and nature of substance transformation within the body by regulating intracellular signal transduction in metabolizing cells and creating 'Targeted Regulators of Xenobiotic/Drug Metabolism' [7,12].…”