Effect of Low-Dose Persistent Organic Pollutants on Mitochondrial Function: Human and in Vitro Evidence

Background@#Chronic exposure to low-dose persistent organic pollutants (POPs) can induce mitochondrial dysfunction. This study evaluated the association between serum POP concentrations and oxygen consumption rate (OCR) as a marker of mitochondrial function in humans and in vitro cells. @*Methods@#Serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in 323 adults. The OCRs of platelets and peripheral blood mononuclear cells (PBMCs) were assessed in 20 mL of fresh blood using a Seahorse XF analyzer. Additionally, the in vitro effects of Arochlor-1254, β-hexachlorocyclohexane, and p,p´-dichlorodiphenyltrichloroethane at concentrations of 0.1 pM to 100 nM were evaluated in human platelets, human PBMCs, and Jurkat T-cells. @*Results@#The association between serum POP concentrations and OCR differed depending on the cell type. As serum OCP concentrations increased, basal platelet OCR levels decreased significantly; according to the OCP quintiles of summary measure, they were 8.6, 9.6, 8.2, 8.0, and 7.1 pmol/min/μg (P trend=0.005). Notably, the basal PBMC OCR levels decreased remarkably as the serum PCB concentration increased. PBMC OCR levels were 46.5, 34.3, 29.1, 16.5, and 13.1 pmol/min/μg according to the PCB quintiles of summary measure (P trend <0.001), and this inverse association was consistently observed in all subgroups stratified by age, sex, obesity, type 2 diabetes mellitus, and hypertension, respectively. In vitro experimental studies have also demonstrated that chronic exposure to low-dose POPs could decrease OCR levels. @*Conclusion@#The findings from human and in vitro studies suggest that chronic exposure to low-dose POPs can induce mitochondrial dysfunction by impairing oxidative phosphorylation.

A randomized, open-label, single-dose, two-way crossover study to assess the pharmacokinetics between two tablets of fixed-dose combination formulation with raloxifene and cholecalciferol and concomitant administration of each agents in healthy male volunteers

A new fixed-dose combination (FDC) formulation of raloxifene 60 mg and cholecalciferol 800 IU was developed to improve the medication compliance and overall efficacy of raloxifene treatment in postmenopausal osteoporosis patients. The aim of this study was to compare the pharmacokinetics between two tablets of FDC formulation of raloxifene/cholecalciferol and the two products administered concomitantly at respective doses. This randomized, open-label, single-dose, two-treatment, two-way crossover study included 46 volunteers. During each treatment period, subjects received the test formulation (FDC formulation containing raloxifene and cholecalciferol) or the reference formulation (co-administration of raloxifene and cholecalciferol), with a 14-d washout period. Serial blood samples were collected periodically over 96 hours after drug intake. In total, 46 subjects completed the study. The geometric mean ratios and its 90% confidence intervals of the FDC to the single agents for the area under the concentration-time curve from zero to the last quantifiable time point and the maximum plasma concentration met the regulatory criteria for bioequivalence: 1.1364 (1.0584–1.2201) and 1.1010 (0.9945–1.2188) for raloxifene and 1.0266 (0.9591–1.0989) and 1.0354 (0.9816–1.0921) for baseline-corrected cholecalciferol, respectively. Both formulations were well tolerated. No significant differences was observed in the incidence of adverse events between the two treatments. It was concluded that two tablets of the newly developed FDC formulation of raloxifene and cholecalciferol and the corresponding two agents administered concomitantly at respective doses were bioequivalent.

Lessons from a multicenter clinical trial with an approved wearable electrocardiogram: issues and practical considerations

Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial.

The possibility of low isomerization of β-lapachone in the human body

β-Lapachone has been reported to have anticancer and various other therapeutic effects, but is limited in clinical applications by its low bioavailability. pH-Dependent isomerization can be suggested as one plausible factor influencing its low bioavailability. Since it is known that β-lapachone is converted to its isomer, α-lapachone in hydrochloric acid (HCl) solution, isomerization in the human body may be driven by HCl in the gastric fluid. The purpose of this study was to evaluate the possibility of isomerization of β-lapachone in the human body. Chemical reactions were conducted using simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.5) at 37°C. β-Lapachone was observed in SGF at 37°C for 1 hour and SIF for 3 hours. In addition, biofluid analysis was performed on plasma samples 1 hour and 4 hours, and on urine sample 12 hours after oral administration of 100 mg MB12066, a synthetic β-lapachone, in healthy adult male. All samples were analyzed using liquid chromatography-tandem mass spectrometry. Only β-lapachone peaks existed in the spectra obtained from SGF and SIF. No isomerization of β-lapachone was observed in the analysis of any of the human samples. In the current study, the possibility of pH-dependent isomerization of β-lapachone in the human body was not confirmed.

Pharmacokinetics and bioequivalence of fixed-dose combination of candesartan cilexetil/amlodipine besylate (16/10 mg) versus coadministration of individual formulations in healthy subjects

This study compared the pharmacokinetics of a fixed-dose combination (FDC) of candesartan (16 mg) and amlodipine (10 mg) versus coadministration of individual formulations to clarify the bioequivalence of the FDC. In this randomized, open-label, single-dose, 2-treatment, 2-way crossover study, healthy Korean volunteers received a single dose of candesartan (16 mg) with amlodipine (10 mg) as either an FDC or single agents concomitantly administered, with a 2-week washout period. Serial blood samples were collected up to 72 hours after dosing for each treatment period, and plasma concentrations of candesartan and amlodipine were measured using a validated liquid chromatography-tandem mass spectrometry method. A total of 39 subjects completed the study. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the peak plasma concentration (Cmax) for candesartan were 1.0182 (0.9562–1.0841) and 0.9492 (0.8726–1.0324), respectively. The GMR and 90% CI for the AUC0-t and Cmax for amlodipine were 1.0552 (1.0255–1.0857) and 1.0668 (1.0259–1.1094), respectively. In conclusion, the new FDC formulation of candesartan (16 mg) and amlodipine (10 mg) was bioequivalent to the concomitant administration of single agents. A single dose of candesartan/amlodipine as the FDC or as single agents was well tolerated.

Understanding the pharmacokinetics of reversible metabolism

This tutorial introduces the mathematical skills required to obtain exact and approximate solutions for reversible reactions and provides graphical insights to help understand the pharmacokinetics of reversible metabolism. The matrix method provides an easy way to derive the exact solution for the amount of each species as a function of time. The plots of the exact solutions reveal some characteristic features of the pharmacokinetic profiles of the reversible metabolism. We also describe two approximation approaches, steady-state approximation, and equilibrium approximation, to simplify the solutions. The skills and knowledge acquired through this tutorial will provide a basis for understanding more complex reversible reaction systems.

Metabolic Profiling of Plasma from Pancreatic Cancer Patients in Korea / 대한췌담도학회지

BACKGROUND/AIMS: Pancreatic cancer (PC) patients have poor prognoses because this cancer is typically diagnosed at an advanced stage and the therapeutic options are limited. We examined the potential of metabolic profiling for early diagnosis and identification of potential therapeutic targets. METHODS: Ten patients and 10 healthy volunteer controls older than 20 years of age were enrolled between May and December 2015. The patients were confirmed to have pancreatic ductal adenocarcinoma cytologically or histologically. Blood plasma samples were derivatized and analyzed by gas chromatography mass spectrometry (GC-MS). Untargeted GC-MS data were analyzed using statistical methods, including Wilcoxon rank-sum test and principal component analyses. RESULTS: L-lysine was 1.36-fold higher in patients than in healthy controls (p<0.05). L-leucine was 0.63-fold lower (p<0.01) and palmitic acid was 0.93-fold lower (p<0.5) in patients than in controls. Orthogonal partial least squared-discriminant analysis revealed significant differences between the patients and controls. CONCLUSIONS: This study suggests that the metabolic profiles of patients with PC are distinct from those of the healthy population. Further studies are required to develop methods for early diagnosis and identify therapeutic targets.

Understanding the pharmacokinetics of prodrug and metabolite

This tutorial explains the pharmacokinetics of a prodrug and its active metabolite (or parent drug) using a two-step, consecutive, first-order irreversible reaction as a basic model for prodrug metabolism. In this model, the prodrug is metabolized and produces the parent drug, which is subsequently eliminated. The mathematical expressions for pharmacokinetic parameters were derived step by step. In addition, we visualized these expressions to help understand the relationship between pharmacokinetic parameters easily. For the elimination rate-limited and formation rate-limited metabolism, we analyzed the plasma drug concentration versus time curve of a prodrug administered intravenously.

Metabolomic analysis of healthy human urine following administration of glimepiride using a liquid chromatography-tandem mass spectrometry

Glimepiride, a third generation sulfonylurea, is an antihyperglycemic agent widely used to treat type 2 diabetes mellitus. In this study, an untargeted urinary metabolomic analysis was performed to identify endogenous metabolites affected by glimepiride administration. Urine samples of twelve healthy male volunteers were collected before and after administration of 2 mg glimepiride. These samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and then subjected to multivariate data analysis including principal component analysis and orthogonal partial least squares discriminant analysis. Through this metabolomic profiling, we identified several endogenous metabolites such as adenosine 3′, 5′-cyclic monophosphate (cAMP), quercetin, tyramine, and urocanic acid, which exhibit significant metabolomic changes between pre- and posturine samples. Among these, cAMP, which is known to be related to insulin secretion, was the most significantly altered metabolite following glimepiride administration. In addition, the pathway analysis showed that purine, tyrosine, and histidine metabolism was affected by pharmacological responses to glimepiride. Together, the results suggest that the pharmacometabolomic approach, based on LC-MS/MS, is useful in understanding the alterations in biochemical pathways associated with glimepiride action.

Determination of sumatriptan in human plasma using liquid chromatography-mass spectrometry for pharmacokinetic study in healthy Korean volunteers

This study describes the development of an analytical method to determine sumatriptan levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) and its application to a pharmacokinetic study in healthy Korean volunteers. A single 50 mg dose of sumatriptan was orally administered to twelve healthy volunteers (nine women and three men). The HPLC-MS/MS analytical method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear over a concentration range of 0.3–100 ng/mL (r > 0.999). The lower limit of quantitation for sumatriptan in plasma was 0.3 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. We compared plasma concentration-time curves as well as pharmacokinetic parameters such as the area under the curve (AUC) and maximum plasma concentration (C(max)). Both the mean AUC and C(max) of sumatriptan were 1.56 times higher in women than in men. These differences could be largely explained by the difference in body weight (44%) between women and men. The outcomes may provide insights into developing appropriate individualized treatment strategies.

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared the pharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) and healthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease of blood pressure (BP) was not clinically significant in those with moderate hepatic impairment. The aims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartan and to evaluate the effect of hepatic function on BP reduction by fimasartan using previously published data. A 2-compartment linear model with mixed zero-order absorption followed by first-order absorption with a lag time adequately described fimasartan PK, and the effect of fimasartan on BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD model overlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model, the lower BP responses in hepatic impairment were the result of the increased fimasartan EC₅₀ in patients, rather than from a saturation of effect. This is congruent with the reported pathophysiological change of increased plasma ACE and renin activity in hepatic cirrhosis.

Development and validation of analytical method for the determination of radotinib in human plasma using liquid chromatography-tandem mass spectrometry

This study describes the development of an analytical method to determine radotinib levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) for pharmacokinetic application. Plasma samples were sequentially processed by liquid-liquid extraction using methyl tert-butyl ether, evaporation, and reconstitution. Analytes were separated and analyzed using HPLC-MS/MS in selected reaction monitoring mode, monitoring the specific transitions of m/z 531 to 290 for radotinib and m/z 409 to 238 for amlodipine (internal standard). The HPLC-MS/MS analytical method was validated with respect to selectivity, linearity, sensitivity, accuracy, precision, recovery, and stability. Calibration curves were linear over a concentration range 5–3,000 ng/mL with correlation coefficients (r) > 0.998. The lower limit of quantification for radotinib in plasma was 5 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. This method was suitable to determine radotinib levels in human plasma because of its simplicity, selectivity, precision, and accuracy.

Deficiency of Lipocalin-2 Promotes Proliferation and Differentiation of Osteoclast Precursors via Regulation of c-Fms Expression and Nuclear Factor-kappa B Activation

BACKGROUND: Lipocalin-2 (LCN2), a small glycoprotein, has a pivotal role in diverse biological processes such as cellular proliferation and differentiation. We previously reported that LCN2 is implicated in osteoclast formation induced by receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). In the present study, we used a knockout mouse model to further investigate the role of LCN2 in osteoclast development. METHODS: Osteoclastogenesis was assessed using primary bone marrow-derived macrophages. RANKL and M-CSF signaling was determined by immunoblotting, cell proliferation by bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay (ELISA), and apoptosis by cell death detection ELISA. Bone morphometric parameters were determined using a micro-computed tomography system. RESULTS: Our results showed that LCN2 deficiency increases tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclast formation in vitro, a finding that reflects enhanced proliferation and differentiation of osteoclast lineage cells. LCN2 deficiency promotes M-CSF-induced proliferation of bone marrow macrophages (BMMs), osteoclast precursors, without altering their survival. The accelerated proliferation of LCN2-deficient precursors is associated with enhanced expression and activation of the M-CSF receptor, c-Fms. Furthermore, LCN2 deficiency stimulates the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), key transcription factors for osteoclastogenesis, and promotes RANKL-induced inhibitor of kappa B (IkappaBalpha) phosphorylation. Interestingly, LCN2 deficiency does not affect basal osteoclast formation in vivo, suggesting that LCN2 might play a role in the enhanced osteoclast development that occurs under some pathological conditions. CONCLUSIONS: Our study establishes LCN2 as a negative modulator of osteoclast formation, results that are in accordance with our previous findings.

Development and validation of a UPLC-MS/MS method for the quantification of acetaminophen in human plasma and its application to pharmacokinetic studies

We developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of acetaminophen concentration in human plasma. Following protein precipitated extraction, the analytes were separated and analyzed using an UPLC-MS/MS in the multiple reaction monitoring (MRM) mode with the respective [M+H]+ ions, m/z 152.06 → 110.16 for acetaminophen and m/z 180.18 → 138.12 for phenacetin (internal standard, IS). The method showed a linear response from 1 to 100 µg/mL (r > 0.9982). The limit of quantitation for acetaminophen in plasma was 1 µg/mL. The intra- and inter-day accuracy ranged in the ranges of 94.40–99.56% and 90.00–99.20%, respectively. The intra- and inter-day precision ranged in the ranges of 2.64–10.76% and 6.84–15.83%, respectively. This method was simple, reliable, precise and accurate and can be used to determine the concentration of acetaminophen in human plasma. Finally, this fully validated method was successfully applied to a pharmacokinetic study of acetaminophen in healthy volunteers following oral administration.

Effects of 12-week Vegetarian Diet on the Nutritional Status, Stress Status and Bowel Habits in Middle School Students and Teachers

This study investigated the effect of switching normal diet to vegetarian diet rich in vegetables and fruits for school foodservice and home meal on the nutritional status, bowel habit improvement and stress reduction of teachers and adolescents. A total of 40 research subjects (26 students, 14 teachers) from one middle school voluntarily participated in the research. Questionnaire surveys and blood analysis were conducted before and after a 12-week vegetarian diet period. The participants were asked on their dietary habit, bowel habit and stress measurement. After 12 weeks, reduction of BMI (kg/m2) in the students (p < 0.05) and reduction of TC (mg/dL) in both teachers and students (p < 0.05) were observed. Also reduction of LDL-C (mg/dL) was observed in the teachers (p < 0.05) whereas serum calcium and Vitamin B12 was increased in the students and teachers (p < 0.005). The teacher's stress level was reduced (p < 0.05) after the 12-week vegetarian diet. As for the changes in bowel habit, the number of the students and teachers classified as experiencing functional constipation was decreased respectively from 10 to 7, from 7 to 5. Based on the result, it is considered that the vegetarian diet rich in fruits and vegetables improved general health status of study subjects suggesting that such a dietary habit would substantially contribute to improving nutritional status and bowel habit.

Serious adverse events during clinical trial for pharmacokinetic interaction between telmisartan and chlorthalidone in healthy Korean subjects: A case report

Telmisartan is an angiotensin II receptor antagonist and chlorthalidone is a thiazide-like diuretics. In this study, we report serious adverse events (SAEs) during clinical trial for pharmacokinetic interaction between telmisartan and chlorthalidone in healthy Korean subjects. Two separate, randomized, multiple-dose, two-period, one-sequence studies were conducted at Kyungpook National University Hospital. In part A, 43 volunteers received telmisartan for 7 days, and then chlorthalidone for 14 days (days 8-21). Telmisartan was co-administered during day 15-21 to evaluate the effects of chlorthalidone on the pharmacokinetics of telmisartan at steady state. A healthy 36-year-old male in part A was referred to the emergency room due to severe nausea and vomiting developed about 3 h after administration of chlorthalidone on day 9. Hypokalemia and QT prolongation were observed during his initial laboratory examination and electrocardiogram (ECG) monitoring in the emergency unit. Nausea and vomiting improved after conservative management with hospitalization for 9 days. We consider that the episodes of excessive nausea and vomiting resulted in hypokalemic state which was potentiated by chlorthalidone. And the hypokalemic state caused the lengthening of the QT interval on ECG.

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

The objective of this study was to develop a population pharmacokinetic (PK) model for sumatriptan, which frequently shows an atypical absorption profile with multiple peaks. Sumatriptan, a selective agonist for the vascular serotonin (5-HT1) receptor that causes vasoconstriction of the cerebral arteries, is used for the acute treatment of migraine attack with or without aura. Despite its relatively high between-subject variability, few reports have addressed PK modeling of sumatriptan. Plasma data obtained after a single 50-mg oral dose of sumatriptan in 26 healthy Korean male subjects were used. Blood samples were collected 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after dosing. Plasma sumatriptan concentrations were analyzed using UPLC/MS/MS. Population PK analysis was performed using plasma concentration data for sumatriptan with NONMEM (ver. 7.2). A total of 364 concentrations of sumatriptan were captured by a one-compartment model with first-order elimination, and a combined transit compartment model and first-order absorption with lag time was successful in describing the PK with multiple peaks in the absorption phase of sumatriptan. The creatinine clearance as a covariate significantly (P < 0.01) influenced the absorption fraction (f ). The final model was validated through a visual predictive check and bootstrapping with no serious model misspecification.

Pharmacometabolomics: Current Applications and Future Perspectives

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.

Effects of Age and Sex on the Pharmacokinetics of Tacrolimus during Pediatric Kidney Transplantation: A Single Center Study

PURPOSE: The pharmacokinetics of tacrolimus, one of the most widely used immunosuppressive drugs, are known to vary by sex, age, and ethnicity during pediatric transplantation. This study assessed the pharmacokinetic characteristics and associated factors of tacrolimus in Korean children receiving a kidney transplant. METHODS: We retrospectively reviewed the pharmacokinetic data (therapeutic dose, trough level, clearance, and half-life) of 9 children who were given tacrolimus as one of their initial immunosuppressive drugs after kidney transplantation. In addition, we compared the findings to data from 10 adult kidney transplant recipients. RESULTS: The mean age of our pediatric patients was 13.9 years, and the male-to-female ratio was 4:5. The mean dose of tacrolimus was 0.19+/-0.14 mg/kg/day. The mean dose of tacrolimus for males was 0.23+/-0.12 mg/kg/day, which was significantly higher than the dose for females (0.16+/-0.14 mg/kg/day). The trough level was not significantly different between both groups. The clearance rate of tacrolimus for males was also significantly higher than females. Although the dosage of tacrolimus for patients over the age of 12 years was lower (0.18+/-0.13 vs. 0.21+/-0.16 mg/kg/day) and the trough level was higher (8.2+/-4.5 vs. 7.2+/-4.2 mg/mL) than that for patients under the age of 12 years, there was no significant difference between them. However, there were significant differences between children and adults in dose, clearance, and half-life of tacrolimus. CONCLUSION: Out study suggests that the pharmacokinetics of tacrolimus tends to vary with sex and age. Therefore, large-scale prospective studies are required to verify the proper therapeutic dosage of tacrolimus in Korean children.

A Study on Current Status of Clinical Trial Pharmacy in Domestic Clinical Trial Institution

BACKGROUND: There is a lack of research on the status of clinical trial pharmacy and clinical trial pharmacist (CTP) in Korea. This study was aimed to investigate the current status of clinical trial pharmacy and clinical trial pharmacists. METHODS: The survey was performed using the 41-item questionnaire designed to investigate information on the following; (1) current status of clinical trial pharmacy designated by Korea Food and Drug Administration, (2) current status of working condition, management, and satisfaction index of CTP. Data collected was analyzed by t-test and chi2. RESULTS: Among the CTPs who responded, 92.7% belonged to department of pharmacy, and 7.3% to clinical trial center. 90.2% of the respondents were women. Forty-two point seven percents of the respondents had more than 3 years of experience in the clinical trial field. 36.6% answered that the current number of CTPs in the institution was '2'. Sixty-three point four percents answered that they subsumed an additional post. Regarding the question on "whether the equipment and working environment of your clinical trials pharmacy is adequate", 65.1% of the respondents answered as 'Inadequate'. Ninety-eight point eight percents answered that work-related education is needed. Ninety-three point nine percents answered that the quality of clinical trials is related to the improvement of the working environment of CTP. CONCLUSION: Clinical trial pharmacy's facility and number of actually working CTP were insufficient. Proper and continuous education and training for CTPs are needed to improve the quality of clinical trials conducted in Korea, with strong institution support and timely regulation change.