The Potential Role of POR*28 and CYP1A2*F Genetic Variations and Lifestyle Factors on Clozapine and N-DesmethylClozapine Plasma Levels in Schizophrenia Patients

ABSTRACT

Background

Despite its advantages over other antipsychotics, for treatment-resistant schizophrenia, clinical use of Clozapine (CLZ) is challenging by its narrow therapeutic index and potentially life-threatening dose-related adverse effects.

Research design and methods

As the potential role in CLZ metabolism is assigned to CYP1A2 enzyme and consequently Cytochrome P450 oxidoreductase (POR) their genetic variations might help to determine CLZ levels in schizophrenia patients. For this purpose, 112 schizophrenia patients receiving CLZ were included in the current study. Plasma CLZ and N-desmethylclozapine (DCLZ) levels were analyzed by using HPLC and genetic variations were identified with the PCR-RFLP method.

Results

The patients’ CYP1A2 and POR genotypes seemed to not affect plasma CLZ and DCLZ levels whereas in the subgroup analysis, POR *28 genotype significantly influenced simple and adjusted plasma CLZ and DLCZ levels concerning smoking habit and caffeine consumption.

Conclusions

The findings of the present study highlight the importance of both genetic and non-genetic factors (smoking and caffeine consumption) for the individualization of the CLZ treatment. In addition to that, it suggests that the added utility of not only the CLZ metabolizing enzymes but also POR, which is crucial for proper CYP activity, to guide CLZ dosing might be useful for clinical decision-making.

KEYWORDS:

• Clozapine
• CYP1A2
• Cytochrome P450 oxidoreductase (POR)
• drug metabolism
• pharmacogenetics
• precision medicine

Author contribution statement

All authors made substantial contributions to the conception and design of the data or the analysis and interpretation of the results. M. Demirbugen Oz conducted the analysis and interpretation of the data and designed the draft of the paper. F. Ozdemir collected biological samples and conducted the genetic analysis. K C. Tok contributed to the management of biological samples and the determination of plasma levels. E. Dural participated in the sample collection and determination of plasma levels. Y. Kir provided clinical data of the diagnosed patients. M. Ulusoy provided clinical data of the diagnosed patients. M. Gumustas contributed to the management of biological samples and the determination of plasma levels. B. Baskak provided medical supervision. S. Suzen performed the conception and design and designed the draft of the paper.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by a Grant from the Ankara University Scientific Projects Coordination Unit [18L0217001].