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    Determination of Mirtazapine and Desmethyl Mirtazapine in Human Plasma by a New Validated HPLC Ultraviolet Method with a Simple and Reliable Extraction Method: Application to Therapeutic Drug Monitoring Study by 62 Real Patient Plasma
    (Shaheed Beheshti Univ, Sch Pharmacy, 2020) Dural, Emrah; Baskak, Nilay Sedes; Ozcan, Hatice; Kir, Yagmur; Baskak, Bora; Suzen, Halil Sinan
    Determination of mirtazapine (MRP) during psychopharmacotherapy in biological fluids is essential to achieve successful therapy, to avoid toxicity related to drug interactions, genetic variability, and poor compliance. A new, rapid, and sensitive high-performance liquid chromatography method has been developed in human plasma for the determination of MRP and N-desmethylmirtazapine (NDM) that is an active metabolite. The separation was achieved on a reverse-phase C18 250 x 4.6 mm i.d., ODS-3 column using programmed gradient elution at 40 degrees C. 20 mM potassium phosphate buffer (pH 3.9), acetonitrile, and triethylamine (75.0:24.9:0.1, v/v/v) were used as mobile phase A. Mobile phase B consisted of absolute acetonitrile. Clozapine was used as an internal standard The method showed linearity with good determination coefficients (r(2)>= 0.9981) for each analyte. Intra-day and interday assay precisions (RSD%) were found less than 3.4 and 2.9 for MRP and NDM, respectively. The intraday and interday accuracy (RE%) of the method were calculated between (-2.8) and 5.5. A new extraction method was used in the study and an excellent recovery (average) values for MRP and NDM (94.4%, 106.6%, respectively) was obtained. The method was specific and sensitive as the limit of detection (LOD) were 0.17 for MRP and 0.15 ng/mL for NDM. This method was applied properly to plasma samples taken from patients receiving MRI (n = 62) treated with 15-30 mg / day. The obtained and statistically evaluated plasma MRP and NDM levels which were 28.6 +/- 13.8 and 12.3 +/- 6.5 (mean +/- SD). The described procedure is relatively simple, precise, and applicable for routine therapeutic drug monitoring especially in psychiatry clinics and toxicology reference laboratories.
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    The Association of CYP2D6*4 and POR*28 Polymorphisms on Mirtazapine Plasma Level in Subjects with Major Depressive Disorder and Anxiety Disorders
    (Bentham Science Publ Ltd, 2020) Ozdemir, Fezile; Dural, Emrah; Baskak, Nilay Sedes; Kir, Yagmur; Baskak, Bora; Suzen, Halt S.
    Aims and Objective: The plasma level of mirtazapine (MIR) varies between individuals primarily depending on the differences in metabolism during pharmacotherapy. CYP2D6 takes the role as a major enzyme in MIR metabolism and POR enzyme donates an electron to CYP2D6 for its activity. Single nucleotide polymorphisms in the genes encoding phamacokinetic enzymes may cause changes in enzyme activity, leading to differences in metabolism of the drug. Our aim was to assess the influence of CYP2D6*4 and POR*28 polymorphisms on MIR plasma levels in Turkish psychiatric patients. Materials and Methods: The association between genetic variations and plasma level of MIR was investigated on 54 patients. CYP2D6*4 and POR*28 polymorphisms were analysed using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) and plasma MIR levels were measured using HPLC. Results: Allele frequencies of CYP2D6*4 and POR*28 were 0.11 and 0.39, respectively in the study population. The results showed that CYP2D6*4 allele carriers have higher C/D MIR levels while POR*28 allele carriers have lower C/D MIR levels. Combined genotype analyses also revealed that individuals with CYP2D6*1/*1 - POR*28/*28 genotype have a statistically lower CID MIR level (0.95 ng/ml/dose) when compared with individuals with CYP2D6*1/*1 - POR*1/*1 genotype (1.52 ng/ml/dose). Conclusion: Our results indicate that CYP2D6*4 and POR*28 polymorphisms may have a potential in the explanation of differences in plasma levels in MIR treated psychiatric patients. A combination of these variations may be beneficial in increasing drug response and decreasing adverse drug reactions in MIR psychopharmacotherapy.
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    The effects of UGT1A4 and ABCB1 polymorphisms on clozapine and Ndesmethyl clozapine plasma levels in Turkish schizophrenia patients
    (Academic Press Inc Elsevier Science, 2025) Ozdemir, Fezile; Oz, Merve Demirbugen; Tok, Kenan Can; Dural, Emrah; Kir, Yagmur; Gumustas, Mehmet; Baskak, Bora
    Clozapine (CLZ) is an antipsychotic which is particularly used in treatment resistant schizophrenia patients who do not respond to other agents. It is preferred because it reduces suicidal behaviours and attempts, reducing aggression and violent behaviour. The aim of the study is to evaluate the effects of ABCB1 rs1045642 and UGT1A4 rs2011425 polymorphisms on CLZ and its major metabolite Ndesmethly clozapine (DCLZ) plasma concentrations in patients with schizophrenia. A total 109 of Turkish patients with schizophrenia on continually administered CLZ monotherapy were included. The plasma concentrations of CLZ and DCLZ were measured using an HPLC after liquid-liquid extraction while, transporter gene ABCB1 and phase two enzyme UGT1A4 polymorphisms were identified using PCR- RFLP method. Results showed that UGT1A4*3 polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while ABCB1 C3435T polymorphism has a significant effect on CLZ/DCLZ ratio among patients who have subtherapeutic levels. This study indicates the influence of genetic differences on plasma levels and highlights the importance of pharmacogenetic studies in clinic. Using the obtained results as pharmacogenetic biomarkers will help clinicians provide effective treatment in individual patients and reduce the undesirable side effects.
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    The Potential Role of POR*28 and CYP1A2*F Genetic Variations and Lifestyle Factors on Clozapine and N-DesmethylClozapine Plasma Levels in Schizophrenia Patients
    (Taylor & Francis Ltd, 2023) Oz, Merve Demirbugen; Ozdemir, Fezile; Tok, Kenan Can; Dural, Emrah; Kir, Yagmur; Ulusoy, Muge; Gumustas, Mehmet
    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.