Association of Plasma Clozapine Level with CYP1A2 -163C/A and CYP2C19 681G/A Gene Polymorphisms in Taiwanese Psychotic Patients Yu-Li Hospital
臺灣精神病患者血漿中氯氮平藥物濃度與CYP1A2 -163C/A及 CYP2C19 681G/A基因多型性相關
Hui-Ching Huang1,2, Bo-Jian Wu3, Ahai C. Lua4, Lawrence Shih-Hsin Wu5, Shin-Min Lee3, Chao-Zong Liu2*
黃輝慶1,2，吳百堅3，賴滄海4，吳世欣5，李新民3，劉朝榮2*
1 Department of pharmacy, Yuli hospital, DOH . 2 Department of Pharmacology, School of Medicine, Tzu Chi University3Department of General Psychiatry, Yuli Hospital, DOH. 4 Department of Laboratory Medicine and Biotechnology, Tzu Chi University5 Institute of Medical Science, Tzu Chi University
1.衛生署玉里醫院藥劑科2.慈濟大學藥理學科3.衛生署玉里醫院精神科4.慈濟大學醫學檢驗生物技術學系5.慈濟大學醫學研究所
Background
The enzymes responsible for clozapine metabolism in human body include CYP1A2 and CYP2C19 whose activities have been shown associated with their gene polymorphisms. This study aims to investigate whether the gene polymorphisms of CYP1A2 (-163C/A) and CYP2C19 (681G/A) correlate with the plasma concentration of clozapine in Taiwanese psychotic patients.
Subjects and Methods Fig.1.The relationship between the plasma concentration of clozapine and gene
One hundred and forty six hospitalized schizophrenic patients were
polymorphisms of CYP1A2 (-163C/A) and CYP2C19 (681G/A). The broken line with
enrolled in this study. They had taken clozapine for at least 14 days.
different colors represent the tendency of simple regression of scatters in patient groups
Whole blood was collected in the morning before drug administration and then subjected to high speed centrifugation for the preparation of plasma. The plasma level of clozapine was determined by LC-MS-MS and the genetic polymorphisms of CYP1A2 and CYP2C19 were analyzed by DNA sequencing and TaqMan genotyping technique, respectively. The relationship between the genotype and plasma concentration of clozapine was determined by multiple-linear regression analysis.
As shown in Fig.1, the patients with the genotype of homozygous - 163A/A ( CYP1A2) exhibited a higher concentration of clozapine in
Fig.2. Effect of smoking on the plasma level of clozapine.The broken line represents
plasma as compared with the subjects bearing homozygous -
tendency of simple regression of scatter. The patients with (n=67) and without (n=79) smoking habits are shown with blue and white circles, respectively.
163C/C ( CYP1A2) (P=0.014), whereas no difference was found between the patients with homozygous 681G/G (CYP2C19) and homozygous 681A/A (CYP2C19). These results indicate that the difference in the plasma level of clozapine was associated with the CYP1A2 gene -163C/A dimorphism but not related to the CYP2C19 gene 681G/A dimorphism. It has been reported that the activity of CYP1A2 can be enhanced by smoking. In this study, we found the plasma clozapine level in non-smokers appears to be higher than those in smokers (P=0.034) (Fig.2). Moreover, only the patients with the A allele were affected by smoking (Fig.3). Conclusion
There is a correlation between the plasma level of clozapine and CYP1A2 gene -163C/A dimorphism in Taiwanese psychotic
Fig.3. Effect of smoking on the plasma concentration of clozapine in patients with different
patients. The patients with the A allele tend to metabolize clozapine
CYP1A2 (-163C/A) genotypes. (A) and (C) show the relationship between the plasma
with a slower rate, which might be enhanced by smoking. Our
concentration of clozapine and the CYP1A2 gene -163C/A dimorphism in non-smoking
results suggest that a lower dosage of clozapine might be good
patient group (AA, n=38; AC, n=37; CC, n=4). (B) and (D) show the relationship between the plasma concentration of clozapine and the CYP1A2 gene -163C/A dimorphism in
enough for this kind of Taiwanese psychotic patients without
smoking patient group (AA, n=21; AC, n=38; CC, n=8). Circles are colorized in different
color according to genotype. The dashed line in each plot represents the best-fit straight line from linear regression analysis.
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Association of Plasma Clozapine Level with CYP1A2 -163C/A and