BRIEF REPORT
The Influence of the CYP3A4*22 Polymorphism on Serum Concentration of Quetiapine in Psychiatric Patients Karen van der Weide, PhD* and Jan van der Weide, PhD*Þ
Background: Besides dietary, hormonal, or pathological factors, mutations in cytochrome P450 enzymes are thought to be responsible for the interindividual differences in serum concentrations of cytochrome P450 (CYP450)Ydependent drugs. Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, a new single-nucleotide polymorphism (SNP) was found (CYP3A4*22), which results in a decreased enzyme activity, in contrast to the other known SNPs in CYP3A4. We investigated to which degree the CYP3A4*22 SNP affects serum concentrations of patients receiving quetiapine, a drug exclusively metabolized by CYP3A4. Methods: Two hundred thirty-eight adult patients receiving quetiapine were included in this study, based on availability of DNA, serum quetiapine levels, and information on dose. Patients were genotyped for CYP3A4*22 using allele-specific polymerase chain reaction, and, as a control, restriction fragment length polymorphism analysis. Results: Carriers of the CYP3A4*22 allele (*1/*22 and *22/*22, n = 31) had 2.5-fold higher serum levels of quetiapine than did wild-type patients (n = 207; P = 0.03) when using a comparable dose (median, 300 mg/d for both wild-type and carriers; P = 0.67). The dose-corrected serum concentration (C/D) was 67% higher in carriers than in wild-type patients (P = 0.01). The number of patients who achieved serum levels above the therapeutic range (9500 Hg/L) was also higher in *22-allele carriers (16.1% vs 2.9%; P = 0.007). Conclusion: Being a carrier of the CYP3A4*22 allele increases the serum concentration of quetiapine at comparable doses. Key Words: cytochrome P450 3A4, CYP3A4*22, quetiapine, pharmacogenetics, single-nucleotide polymorphism (J Clin Psychopharmacol 2014;34: 256Y260)
D
espite the availability of a wide range of different psychiatric medications, 30% to 50% of the patients do not respond well to treatment with standard psychiatric medication.1 This difference in response can, at least in part, be explained by interindividual differences in cytochrome P450 (CYP450) activity.2 Cytochrome P450 enzymes are involved in phase 1 metabolism of many drugs. Cytochrome P450 3A4 (CYP3A4), the most abundant CYP enzyme, accounts for the metabolism of about 50% of all prescribed drugs.3 CYP3A4 expression and activity show 10- to 100-fold interindividual variations that affect drug response and toxicity.4Y6 The expression of CYP3A4 can be affected by dietary,7 hormonal,8 or pathological factors,9
From the *St Jansdal Hospital, Department of Clinical Chemistry, Harderwijk; and †Psychiatric Hospital GGz Centraal, location Veldwijk, Ermelo, the Netherlands. Received February 25, 2013; accepted after revision August 30, 2013. Reprints: Jan van der Weide, PhD, Department of Clinical Chemistry, St Jansdal Hospital, Wethouder Jansenlaan 90, 3844 DG, Harderwijk, the Netherlands (e
The Influence of the CYP3A4*22 Polymorphism on Serum Concentration of Quetiapine in Psychiatric Patients Karen van der Weide, PhD* and Jan van der Weide, PhD*Þ
Background: Besides dietary, hormonal, or pathological factors, mutations in cytochrome P450 enzymes are thought to be responsible for the interindividual differences in serum concentrations of cytochrome P450 (CYP450)Ydependent drugs. Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, a new single-nucleotide polymorphism (SNP) was found (CYP3A4*22), which results in a decreased enzyme activity, in contrast to the other known SNPs in CYP3A4. We investigated to which degree the CYP3A4*22 SNP affects serum concentrations of patients receiving quetiapine, a drug exclusively metabolized by CYP3A4. Methods: Two hundred thirty-eight adult patients receiving quetiapine were included in this study, based on availability of DNA, serum quetiapine levels, and information on dose. Patients were genotyped for CYP3A4*22 using allele-specific polymerase chain reaction, and, as a control, restriction fragment length polymorphism analysis. Results: Carriers of the CYP3A4*22 allele (*1/*22 and *22/*22, n = 31) had 2.5-fold higher serum levels of quetiapine than did wild-type patients (n = 207; P = 0.03) when using a comparable dose (median, 300 mg/d for both wild-type and carriers; P = 0.67). The dose-corrected serum concentration (C/D) was 67% higher in carriers than in wild-type patients (P = 0.01). The number of patients who achieved serum levels above the therapeutic range (9500 Hg/L) was also higher in *22-allele carriers (16.1% vs 2.9%; P = 0.007). Conclusion: Being a carrier of the CYP3A4*22 allele increases the serum concentration of quetiapine at comparable doses. Key Words: cytochrome P450 3A4, CYP3A4*22, quetiapine, pharmacogenetics, single-nucleotide polymorphism (J Clin Psychopharmacol 2014;34: 256Y260)
D
espite the availability of a wide range of different psychiatric medications, 30% to 50% of the patients do not respond well to treatment with standard psychiatric medication.1 This difference in response can, at least in part, be explained by interindividual differences in cytochrome P450 (CYP450) activity.2 Cytochrome P450 enzymes are involved in phase 1 metabolism of many drugs. Cytochrome P450 3A4 (CYP3A4), the most abundant CYP enzyme, accounts for the metabolism of about 50% of all prescribed drugs.3 CYP3A4 expression and activity show 10- to 100-fold interindividual variations that affect drug response and toxicity.4Y6 The expression of CYP3A4 can be affected by dietary,7 hormonal,8 or pathological factors,9
From the *St Jansdal Hospital, Department of Clinical Chemistry, Harderwijk; and †Psychiatric Hospital GGz Centraal, location Veldwijk, Ermelo, the Netherlands. Received February 25, 2013; accepted after revision August 30, 2013. Reprints: Jan van der Weide, PhD, Department of Clinical Chemistry, St Jansdal Hospital, Wethouder Jansenlaan 90, 3844 DG, Harderwijk, the Netherlands (e
