Optimization and Validation of an HPLC-UV Method for Analysis of Clozapine and its Major Metabolites in Human Plasma

Dural, Emrah; Mergen, Görkem; Söylemezoğlu, Tülın

doi:10.5505/tjps.2015.68077

Cited by 10 publications

(5 citation statements)

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“…Generally, a polar mobile phase consisting of a mixture of acetonitrile with or without methanol and either ammonium acetate or phosphate buffer with or without triethylamine was selected. Some investigations performed sample clean‐up using LLE [18–20,25–29]. The resulting ERs% of LLE methods ranged between 82.7 and 101% for CLZ and 47.6 and 97.6% for NCLZ, which was comparable to the results of the current method.…”

Section: Resultssupporting

confidence: 64%

Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

Albitar

Murugaiyah

Ibrahim

et al. 2022

Separation Science Plus

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Clozapine is the drug of choice for treatment‐resistant schizophrenia. However, it is characterized by inter‐ and intraindividual variability in plasma concentrations and complex metabolism requiring drug monitoring. A surfactant‐assisted dispersive liquid–liquid microextraction method followed by high‐performance liquid chromatography–ultraviolet is proposed to determine clozapine and its primary active metabolite, norclozapine, in plasma using haloperidol (400 ng/mL) as an internal standard. The surfactant, cetyl trimethyl ammonium bromide (0.5 mmol/L), and 1‐octanol (extraction solvent) were rapidly injected into the diluted plasma to form a cloudy solution. After centrifugation, 50 μL of the organic phase was injected into high‐performance liquid chromatography for analysis. The procedure was optimized by controlling the extraction solvent type and volume, the surfactant type and concentration, pH, and ionic strength. Furthermore, its suitability was investigated using plasma samples obtained from two healthy volunteers following a 12.5 mg dose of clozapine. The analytical performance of the method was acceptable with a limit of quantification of 0.9 and 0.4 ng/mL for clozapine and norclozapine, respectively (r2 > 0.999) and a wide linear dynamic range 6.25–1600 ng/mL. The optimized method is simple, practical, environmentally friendly, and economically acceptable. It also requires a small amount of the sample.

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Section: Resultssupporting

confidence: 64%

Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

Albitar

Murugaiyah

Ibrahim

et al. 2022

Separation Science Plus

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show abstract

“…Protein was precipitated twice, and the collected supernatant was stored at −20 °C. Lastly, a 10 µl portion of the supernatant was injected into the LC-MS system to determine the concentration of parent compound and metabolites 67 . The detection and quantification of clozapine and metabolites was performed using high-performance liquid chromatography (Agilent 1200 Series, Santa Clara CA) coupled with mass spectrometry (TSQ Quantum triple stage quadrupole mass spectrometer; Thermo-Electron, San Jose, CA).…”

Section: Clozapine Metabolism In Single-sex Hlm Poolsmentioning

confidence: 99%

Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

et al. 2023

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Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.

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“…The simplification of this assay makes it ideal for high throughput analyses of the patient samples in a routine clinical laboratory staffed with general medical technologists. [ 4 ]…”

Section: Ethodsmentioning

confidence: 99%

Influence of Cigarette Smoking Habit on Clozapine-to-Norclozapine Ratio in Male Patients

Lozano,

Bona

2023

Journal of Research in Pharmacy Practice

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Objective: This study aimed to evaluate the influence of cigarette smoking habit on the clozapine (CLZ)-to-norclozapine (norCLZ) ratio in male patients. Methods: The sample consisted of plasma concentration of CLZ and norCLZ data set. The mean values of CLZ, norCLZ, and CLZ-to-norCLZ, between male patients who smoke versus nonsmokers were compared. Findings: CLZ mean plasma level of 142 ± 80 ng/ml and 305 ± 159 ng/ml, norCLZ mean plasma level of 93 ± 72 ng/ml and 234 ± 62 ng/ml, and mean CLZ-to-norCLZ plasma level ratio of 2.1 ± 1.1 and 1.5 ± 0.5, were obtained respectively for male patients who smoke and nonsmokers. Conclusion: This study has shown a significant decrease in CLZ and norCLZ plasma levels, and an increase in the CLZ-to-norCLZ ratio, in smokers as compared to nonsmokers, due to an increase in the clearance of CLZ and norCLZ by smoking induction of CYP 1A2 and glucuronidation by uridyl glucuronyl transferase enzymes (UGT), mainly UGT 1A4, respectively, as the most probable cause.

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Optimization and Validation of an HPLC-UV Method for Analysis of Clozapine and its Major Metabolites in Human Plasma

Cited by 10 publications

References 0 publications

Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

Influence of Cigarette Smoking Habit on Clozapine-to-Norclozapine Ratio in Male Patients

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