The influence of the CYP3A4*22 polymorphism on serum concentration of quetiapine in psychiatric patients.

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)-dependent 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 (>500 µg/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.