Effect of a Genetic Polymorphism of CYP1A2 Inducibility on the Steady State Plasma Concentrations of Haloperidol and Reduced Haloperidol in Japanese Patients With Schizophrenia

2000 ◽  
Vol 22 (3) ◽  
pp. 245-249 ◽  
Author(s):  
Kazuo Mihara ◽  
Akihito Suzuki ◽  
Tsuyoshi Kondo ◽  
Norio Yasui ◽  
Hanako Furukori ◽  
...  
Keyword(s):  
Steady State ◽  
Genetic Polymorphism ◽  
Plasma Concentrations ◽  
Japanese Patients ◽  
Reduced Haloperidol ◽  
State Plasma

Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms

2017 ◽  
Vol 54 (6) ◽  
pp. 677-685 ◽  
Author(s):  
Yumiko Akamine ◽  
Yuka Sugawara-Kikuchi ◽  
Tsukasa Uno ◽  
Tetsuo Shimizu ◽  
Masatomo Miura
Keyword(s):  
Steady State ◽  
High Performance ◽  
Plasma Concentrations ◽  
Japanese Patients ◽  
Hplc Method ◽  
Coefficients Of Variation ◽  
Trough Concentrations ◽  
Polymerase Chain ◽  
Cyp 2D6 ◽  
State Plasma

Background This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C0) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia. Methods Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction. Results The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C0/dose (C0/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C0/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C0/D ratios of clozapine ( R2 = 0.139, P = 0.016). Conclusions Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient’s ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure.

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