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Development of a LC-MS/MS for Quantification of Venlafaxine in Human Plasma and Application to Bioequivalence Study in healthy Korean Subjects.

Hyun Ku KANG ; Min A KANG ; Hyun Jin KIM ; Yoo Sin PARK ; Shin Hee KIM ; Ju Seop KANG

Translational and Clinical Pharmacology.2014;22(1):35-42. doi:10.12793/tcp.2014.22.1.35

A simple, rapid and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is developed and validated for quantification of venlafaxine in human plasma with simple liquid-liquid extraction step consisted of extraction with ether and dichloromethane for 10 min and mixing with 1 M sodium acetate in human plasma using fluoxetine as an internal standard (IS). The analyte are separated using an isocratic mobile phase consisted of acetonitrile and 5 mM ammonium formate (4/3, v/v) on a isocratic YMC hydrosphere C18 (2.0x50.0 mm, 3.0 microm) column and analyzed by MS/MS in the multiple reaction monitoring (MRM) mode using the transitions of respective [M+H](+) ions, m/z 278.2-->260.3 and m/z 310.1-->148.1 for quantification of venlafaxine and IS, respectively. The standard calibration curves showed good linearity within the range of 1.0-200.0 ng/mL (r2=0.9986, 1/chi2 weighting). The lower limit of quantification (LLOQ) was 1.0 ng/mL. The retention times of venlafaxine and IS were 0.6 min and 0.7 min that means the potential for the high-throughput potential of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. Acceptable precision and accuracy were obtained for the concentrations over the standard curve range. The validated method was successfully applied to bioequivalence study after 75-mg of venlafaxine sustained-release (SR) capsule in 24 healthy Korean subjects.
Ammonium Compounds ; Calibration ; Chromatography, Liquid ; Ether ; Fluoxetine ; Humans ; Ions ; Liquid-Liquid Extraction ; Methylene Chloride ; Pharmacokinetics ; Plasma* ; Sodium Acetate ; Tandem Mass Spectrometry ; Therapeutic Equivalency* ; Venlafaxine Hydrochloride

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Genetic Polymorphisms of the Carboxylesterase 1 (CES1) Gene in a Korean Population.

Yu Jung CHA ; Hye Eun JEONG ; Jae Gook SHIN ; Eun Young KIM ; Kyung Sang YU ; Joo Youn CHO ; Seo Hyun YOON ; Kyoung Soo LIM

Translational and Clinical Pharmacology.2014;22(1):30-34. doi:10.12793/tcp.2014.22.1.30

Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyzes various exogenous compounds. Single nucleotide polymorphisms (SNPs) of CES1 may lead to inter-individual metabolic variability of its substrates. The allele and haplotype frequencies of known SNPs have been demonstrated to vary among ethnic groups. We analyzed genetic variations of CES1 in a Korean population. Direct sequencing of all exons and flanking regions of the CES1 gene was performed on samples obtained from 200 Koreans. We identified 41 SNPs. The most frequent SNPs was -914G>C (frequency: 99.5%), followed by 4256G>A (frequency: 65.8%), -75T>G (frequency: 59.3%). Haplotype analysis using the identified SNPs revealed fifteen haplotypes (> or =1% haplotype frequency) in our samples. The most frequent haplotype was Hap1 (frequency: 15.4%). Among the identified 41 SNPs, nine of which are novel variants and 14 SNPs were nonsynonymous variants. Using the functional predictive software PolyPhen-2, the G19V, E221G, and A270S variants were predicted to be most likely damaging to the function and structure of CES1. In-vitro analyses for two of these variants have been previously performed; however, functional evaluation of E221G (11657A>G, rs200707504) still needs to be conducted. Therefore, further studies are warranted to characterize the functional impact of E221G on CES1 activity.
Alleles ; Asian Continental Ancestry Group ; Carboxylesterase* ; Ethnic Groups ; Exons ; Genetic Variation ; Haplotypes ; Humans ; Polymorphism, Genetic* ; Polymorphism, Single Nucleotide ; Serine

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Pharmacokinetic Characteristics of Ibandronate and Tolerability of DP-R206 (150 mg Ibandronate/24,000 IU Vitamin D3) Compared to the Ibandronate (150 mg) Monotherapy in Healthy Adults.

Hee Youn CHOI ; Mi Jo KIM ; Yo Han KIM ; Yook Hwan NOH ; Jae Won LEE ; Tae Won LEE ; Min Gul KIM ; Kyun Seop BAE

Translational and Clinical Pharmacology.2014;22(1):22-29. doi:10.12793/tcp.2014.22.1.22

Ibandronate (a bisphosphonate) is commonly used as an treatment of osteoporosis in combination with vitamin D. Monthly DP-R206-a novel, fixed-dose combination tablet (150 mg ibandronate/24,000 IU vitamin D3)-was recently developed to enhance patient compliance. This open, randomized, two-period crossover study was conducted to compare the pharmacokinetics of ibandronate when administered as DP-R206 or 150 mg ibandronate to healthy adult volunteers. Each volunteer was randomly allocated to receive single-dose DP-R206 or ibandronate with a 28-day washout period between treatments. Blood samples were assessed using pharmacokinetic analysis. Plasma ibandronate concentrations were determined using liquid chromatography-tandem mass spectrometry. Safety and tolerability assessments were performed throughout the study. In total, 103 participants received the study drugs and 72 participants completed the study. The geometric mean ratios (DP-R206/ibandronate) of the maximum concentration (C(max)) and the area under the plasma concentration time curve from time zero to the last concentration (AUC(last)) values were 0.959 (90% CI: 0.820-1.120) and 0.924 (90% CI: 0.805-1.060), respectively. The frequencies of adverse events (AEs) and drug reactions were similar between treatment groups, and all AEs were recovered without sequalae. Ibandronate pharmacokinetics, tolerability, and safety are comparable when administered to healthy individuals, regardless if administered as DP-R206 or ibandronate.
Adult* ; Cross-Over Studies ; Humans ; Mass Spectrometry ; Osteoporosis ; Patient Compliance ; Pharmacokinetics ; Plasma ; Vitamin D ; Vitamins* ; Volunteers

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Pregnane X Receptor agonist Increases the Expression Levels of the Plasma Membrane Monoamine Transporter.

Sung Kweon CHO ; Haejin OH ; Se Hyang HONG ; Min Soo PARK ; Jae Yong CHUNG

Translational and Clinical Pharmacology.2014;22(1):19-21. doi:10.12793/tcp.2014.22.1.19

We evaluated the effect of the pregnane X receptor agonist, pregnenolone 16 alpha-carbonitrile (PCN) on the expression levels of plasma monoamine transporter (PMAT) in the intestine. Male C57/BL6 mice were divided into two 2 groups: mice in the PCN group (n=3) were administered PCN once a day for 4 days, while those in the control group (n=3) received the same volume of vehicle once a day for 4 days. After the mice were killed 24 h after administration of the last dose of PCN or vehicle, and the expression levels of PMAT in the intestine tissues were isolated and measured the expression level of PMAT using immunohistochemical and western blotting analyses. The expression level of PMAT expression levels in the small intestine increased after PCN treatment. These results suggest that the induction of PMAT may play a clinically significant role by increasing intestinal absorption of PMAT substrates such as metformin.
Animals ; Blotting, Western ; Cell Membrane* ; Humans ; Intestinal Absorption ; Intestine, Small ; Intestines ; Male ; Metformin ; Mice ; Plasma ; Pregnenolone Carbonitrile

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Clinical Pharmacology Review for Primary Health Care Providers: I. Antihistamines.

Seunghoon HAN

Translational and Clinical Pharmacology.2014;22(1):13-18. doi:10.12793/tcp.2014.22.1.13

Primary health care providers play a critical role in maintaining public health, and the appropriate use of pharmaceutical products is one of the major parts of their practice. This series of articles, entitled 'Clinical Pharmacology Review for Primary Health Care Providers,' is intended to help primary health care providers select more appropriate prescriptions for frequently used drugs based on up-to-date information. We expect that this effort will contribute to improvements in public health and diminish unnecessary drug use.
Histamine Antagonists* ; Pharmaceutical Preparations ; Pharmacology ; Pharmacology, Clinical* ; Prescriptions ; Primary Health Care* ; Public Health

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Repeated Administration of Newly Synthesized Aceclofenac Sustained Release Form Causes Agranulocytosis: Case Report of an Unforeseen Adverse Event during the Phase 1 Trial.

Hui JIN ; Renhua ZHENG ; Bohyung KIM ; Sung Vin YIM

Translational and Clinical Pharmacology.2014;22(1):11-12. doi:10.12793/tcp.2014.22.1.11

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAIDs) for inflammatory diseases. In this report, we report a serious adverse event (AE) occurred during the phase I clinical trial for a new sustained-release (SR) formulation of aceclofenac. There was a serious adverse event (AE), agranulocytosis, induced by aceclofenac SR form. An open-labeled, repeated-doses, randomized, crossover study was conducted at Kyung Hee University Hospital and 26 Korean healthy male volunteers were enrolled. All subjects received both aceclofenac SR 200 mg once daily and aceclofenac IR 100 mg twice daily for 4 days with 11 days washout period. After 11 days washout period, one subject showed a serious decrease in the segment neutrophil (267/mm3) on a laboratory test prior to the reference drug administration in period 2. We first report a case of agranulocytosis, during a phase I clinical trial.
Agranulocytosis* ; Cross-Over Studies ; Humans ; Male ; Neutrophils ; Volunteers

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Pharmacometabolomics: Current Applications and Future Perspectives.

Hyun Ju KIM ; Young Ran YOON

Translational and Clinical Pharmacology.2014;22(1):8-10. doi:10.12793/tcp.2014.22.1.8

Metabolomics, a novel "omics" platform, is a powerful tool for the discovery of clinically useful biomarkers and biochemical processes to improve diagnosis and therapy. Through the use of advanced analytical technologies, metabolomics enables the assessment of comprehensive metabolic profiles that are affected by both genotype and environmental factors. Recently, attention has been focused on the concept of pharmacometabolomics, an emerging field that is derived from metabolomics. Pharmacometabolomics is focused on the use of individual metabolic signatures for the prediction and evaluation of drug efficacy and safety, eventually accelerating clinical pharmacology toward personalized drug therapy.
Biochemical Processes ; Biomarkers ; Diagnosis ; Drug Therapy ; Genotype ; Humans ; Precision Medicine ; Metabolome ; Metabolomics ; Pharmacology, Clinical

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CYP3A5*3 Polymorphism and Its Clinical Implications and Pharmacokinetic Role.

Ji Young PARK ; Yu Jung CHA ; Kyoung Ah KIM

Translational and Clinical Pharmacology.2014;22(1):3-7. doi:10.12793/tcp.2014.22.1.3

The cytochrome P450 (CYP) 3A subfamily is estimated to participate in the biotransformation of 50% of the currently prescribed drugs. Four members of the CYP3A subfamily have been identified in humans: CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Initial data suggested that CYP3A5 accounts for only a small proportion of the total hepatic CYP3A in about 20% of samples, but it was later revealed that CYP3A5 represents more than 50% of the total CYP3A amount in some individuals. Several genetic variants have been described for the CYP3A5 gene, of which the CYP3A5*3 allele (gA6986G), the most common form and leading to the loss of CYP3A5 activity, has been extensively investigated in the aspect of pharmacokinetics and disease risk. This review summarized the molecular characteristics of the CYP3A5 gene, and discusses the association of the CYP3A5*3 polymorphism with disease risks such as cancer and hypertension, along with its role in the pharmacokinetics of CYP3A substrates.
Alleles ; Biotransformation ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System ; Humans ; Hypertension ; Pharmacogenetics ; Pharmacokinetics

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From JKSCPT to TCP.

Dong Seok YIM

Translational and Clinical Pharmacology.2014;22(1):1-1. doi:10.12793/tcp.2014.22.1.1

No abstract available.

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HPLC-UV method for the simultaneous determinations of ascorbic acid and dehydroascorbic acid in human plasma.

Yunjeong KIM ; Min Gul KIM

Translational and Clinical Pharmacology.2016;24(1):37-42. doi:10.12793/tcp.2016.24.1.37

A high performance liquid chromatography (HPLC) paired with UV-vis detection method to determine ascorbic acid and its oxidation product, dehydroascorbic acid, in human plasma was developed. Ascorbic acid in human plasma was extracted and stabilized using 10% metaphosphoric acid, and was analyzed by a Symmetry C18 column with 5 mM Hexadecyltrimethylammonium bromide and 50 mM KH2PO4 solution as the mobile phase (1.0 mL/min flow rate). Isoascorbic acid served as the internal standard and ultraviolet detector wavelength was 254 nm and 265 nm. Dehydroascorbic acid concentration was calculated from the differences in ascorbic acid concentration before and after reduction by dithiothreitol reagent. Quantification for ascorbic acid in human plasma was linear from 1–100 µg/mL. The inter- and intra-day precisions and accuracy were determined and the results were found to be within ±15%. This method was successfully applied to a human pharmacokinetic study of ascorbic acid as well as dehydroascorbic acid after oral administration of 4,000 mg vitamin C tablets to healthy Korean volunteers.
Administration, Oral ; Ascorbic Acid* ; Chromatography, High Pressure Liquid ; Chromatography, Liquid ; Dehydroascorbic Acid* ; Dithiothreitol ; Humans* ; Plasma* ; Tablets ; Volunteers

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