Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders

Abstract

It has been suggested that the reduced function allele with reduced cytochrome P450 (CYP) 2D6 activity, CYP2D6*10, is associated with the interindividual differences in the plasma paroxetine concentrations, but there is no data presently available regarding the influence of the CYP2D6*10 polymorphism on the pharmacokinetic parameters, eg, Michaelis–Menten constant (Km) and maximum velocity (Vmax), in Asian populations. The present study investigated the effects of the CYP2D6 polymorphisms, including CYP2D6*10, on the pharmacokinetic parameters of paroxetine in Japanese patients with major depressive disorders. This retrospective study included 15 Japanese patients with major depressive disorders (four males and eleven females) who were treated with paroxetine. The CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 polymorphisms were evaluated. A total of 56 blood samples were collected from the patients. The Km and Vmax values of paroxetine were estimated for each patient. The allele frequencies of CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 were 6.7%, 0%, 10.0%, 56.7%, 0%, 26.7%, and 0%, respectively. The mean values of Km and Vmax were 50.5±68.4 ng/mL and 50.6±18.8 mg/day, respectively. Both the Km and Vmax values were significantly smaller in CYP2D6*10 allele carriers than in the noncarriers (24.2±18.3 ng/mL versus 122.5±106.3 ng/mL, P=0.008; 44.2±16.1 mg/day versus 68.3±15.0 mg/day, P=0.022, respectively). This is the first study to demonstrate that the CYP2D6*10 polymorphism could affect the nonlinear pharmacokinetic parameter estimates of paroxetine in Asian populations. The findings of this study suggest that the CYP2D6*10 polymorphism may be associated with the smaller values of both the Km and Vmax in Japanese patients with major depressive disorders, and these results need to be confirmed in further investigations with a larger number of patients.

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

“…Targeting AIS function would allow for the development of highly specific, efficacious compounds with significantly reduced off-target effects and enhanced clinical outcomes (13, 140, 141). Given the importance of the molecular composition of the AIS to disease, selective targeting of PPI at the AIS may deliver a new generation of treatments against psychiatric disorders.…”

Identification of CYP2D6 allelic mutations in a sub-set of Karachi population

“…However, in depressed patients it was 1.84x lower than their normal counterparts in Karachi population but closer to depressed patients of UAE and Japanese population (39.1% and 39.4%) [26,29]. It has been proved experimentally that CYP2D6*1 allele in Japanese was closer to Karachiites.…”

“…However, due to the presence of single heterozygous individual (*1/*4) in normal subjects very low or negligible allelic frequency (0.01%) was found in Karachi population. On the contrary, the frequency of CYP2D6*4 was higher in Caucasians (20%) [23,29].…”

Genetic polymorphisms analysis of CYP2D6 in the Uygur population

“…We also found a high frequency of CYP2D6*39 (22.9 %) in the Uygur population, which was different from that in the other ethnic groups and had not been previously described in the Uygur population. The CYP2D6*39 allele was previously reported to be common in Asian populations and to possibly decrease the expression level of the CYP2D6 protein; however, that allele could not transform the protein function [ 19 ].…”