Evaluation of sex differences in the pharmacokinetics of oral sumatriptan in healthy Korean subjects using population pharmacokinetic modeling.

Sumatriptan was introduced in 1983, as the first of the triptans, selective 5-hydroxytryptamine (5-HT1B/1D ) receptor agonists, to treat moderate to severe migraine. Migraine predominates in females. Although there have been reports of sex differences in migraine-associated features and pharmacokinetics (PKs) of some triptans, sex differences in the PKs of oral sumatriptan have never been evaluated in Korean. We conducted this study of oral sumatriptan to assess the sex differences in Korean population. Thirty-eight healthy Korean subjects who participated in two separate clinical studies receiving a single oral dose of 50 mg sumatriptan with the same protocols were included in this analysis. A total of 532 sumatriptan concentration observations were used for a population PK modeling. Validation of final population PK model of sumatriptan was performed using bootstrap and visual predictive check. The PK profile of oral sumatriptan was adequately described by a one-compartmental model with combined transit compartment model and a first-order absorption. The covariate analysis showed that the clearance of oral sumatriptan was significantly higher in males than in females (male: 444 L/h, female: 281 L/h). Our results showed that there were sex differences in the clearance of oral sumatriptan. These results encourage further studies to establish the sumatriptan pharmacokinetic-pharmacodynamic model considering sex-related PK differences, which may help to determine optimal dosing regimens for effective treatment of migraine in males and females. Clinical trial registration: CRIS Registration No. KCT0001784.

Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia.

Clozapine has been used as a treatment of schizophrenia. Despite its large interindividual variability, few reports addressed the physiologically-based pharmacokinetic modeling and simulation (PBPK M&S) of clozapine in patients. This study aimed to develop a PBPK M&S of clozapine in Korean patients with schizophrenia. PBPK modeling for clozapine was constructed using a population-based PBPK platform, the SimCYP® Simulator (V19; Certara, Sheffield, UK). The PBPK model was developed by optimizing the physiological parameters of the built-in population and compound libraries in the SimCYP® Simulator. The model verification was performed with the predicted/observed ratio for pharmacokinetic parameters and visual predictive checks (VPCs) plot. Simulations were performed to predict toxicities according to dosing regimens. From published data, 230 virtual trials were simulated for each dosing regimen. The predicted/observed ratio for the area under the curve and peak plasma concentration was calculated to be from 0.78 to 1.34. The observation profiles were within the 5th and 95th percentile range with no serious model misspecification through the VPC plot. A significant impact on age and gender was found for clozapine clearance. The simulation results suggested that 150 mg twice a day and 150 mg three times a day of clozapine have toxicity concerns. In conclusion, a PBPK model was developed and reasonable parameters were made from the data of Korean patients with schizophrenia. The provided model might be used to predict the pharmacokinetics of clozapine and assist dose adjustment in clinical settings.

Population pharmacokinetic analysis of tramadol and O-desmethyltramadol with genetic polymorphism of CYP2D6.

Aim: Tramadol is widely used to treat acute, chronic, and neuropathic pain. Its primary active metabolite, O-desmethyltramadol (M1), is mainly responsible for its µ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by the cytochrome P450 (CYP) 2D6 enzyme, and to other metabolites by CYP3A4 and CYP2B6. The aim of this study was to develop a population pharmacokinetic (PK) model of tramadol and its metabolite using healthy Korean subjects. Methods: Data on plasma concentrations of tramadol and M1 were obtained from 23 healthy Korean male subjects after a twice-daily oral dose of 100 mg of tramadol, every 12 hrs, for a total of 5 times. Blood samples were collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hrs after last administration. Plasma tramadol concentrations were then analyzed using LC/MS. Population PK analysis of tramadol and its metabolite was performed using a nonlinear mixed-effects modeling (NONMEM). Results: A one-compartment model with combined first-order and zero-order absorption was well fitted to the concentration-time curve of tramadol. M1 was well described by the one-compartment model as an extension of the parent drug (tramadol) model. Genetic polymorphisms of CYP2D6 correlated with the clearance of tramadol, and clearance from the central compartment to the metabolite compartment. Conclusion: The parent-metabolite model successfully characterized the PK of tramadol and its metabolite M1 in healthy Korean male subjects. These results could be applied to evaluate plasma tramadol concentrations after various dosing regimens.

Educational and interactive informed consent process for treatment of unruptured intracranial aneurysms.

OBJECTIVE For patients with unruptured intracranial aneurysms (UIAs), the information transfer that precedes informed consent needs to be in-depth and detailed, as most patients with a UIA have no symptoms, yet the risks related to treatment are relatively high. Thus, in this study an educational and interactive program was proposed for patients with UIAs to improve the informed consent process and assess the level of comprehension. METHODS A total of 110 patients with UIAs underwent the proposed educational and interactive informed consent (EIIC) process and were enrolled in this study. The EIIC process combines patient education using information booklets, a cartoon book, a video, an initial physician-patient interview, answering a questionnaire, a second physician-patient interview based on the questionnaire results, and finally consent. After the first physician-patient interview that provides the patient with specific information, including his or her angiographic characteristics, medical condition, and recommended treatment, the patient is requested to answer a questionnaire composed of 3 parts: demographic information, including the patient's age, sex, and years of education; 13 medical questions to assess the patient's knowledge about his or her UIA; and an evaluation of the usefulness of the educational resources. The control group consisted of 65 patients from 3 other tertiary university hospitals where the EIIC process was not used. RESULTS The questionnaire scores of the EIIC group ranged from 7 to 13 (mean ± SD: 11.9 ± 1.3) and were significantly higher than those for the controls (10.2 ± 1.9, p < 0.001). The better comprehension of the patients in the EIIC group was remarkable as they were significantly older than those in the control group (62.7 ± 8.3 years vs 55.9 ± 10.5 years, respectively; p < 0.001). For both the EIIC group and the control group, a Pearson correlation analysis revealed a positive correlation (r = 0.232 for the EIIC group, r = 0.603 for controls) between the years of education and the questionnaire score (p = 0.015 for the EIIC group, p < 0.001 for the controls), whereas no correlation was found between the patient age and the questionnaire score. For the EIIC group, the verbal information from the attending physician was selected by 90 patients (81.8%) as the most useful and informative educational method, while the most effective reinforcement of this verbal communication was the video (n = 86; 78.2%), information booklets (n = 16; 14.5%), the Internet (n = 7; 6.4%), and the cartoon book (n = 1; 0.9%). CONCLUSIONS The proposed standardized EIIC process resulted in good patient comprehension about UIAs. The verbal information from the attending physician was the most informative, and the video was the most effective reinforcement of the verbal communication. The patient level of comprehension was shown to be correlated with years of education.

Critical Age Affecting Functional Outcome after Decompressive Hemicraniectomy for Malignant Hemispheric Infarction.

OBJECTIVE: Although age already is known as a crucial factor affecting the functional outcome after a hemicraniectomy for malignant hemispheric infarction, previous studies have used arbitrary age cut-offs of 50, 60, or 70 years. Therefore, this study investigated predictors of the functional outcome after a hemicraniectomy and attempted to determine the critical age for an unfavorable functional outcome. METHODS: A total of 38 patients with large hemispheric infarction were treated with a decompressive hemicraniectomy and the corresponding 1-year modified Rankin Scale (mRS) data obtained. An array of clinical variables was then investigated in relation to the functional outcomes. RESULTS: A multivariate analysis that used binary multiple logistic regression revealed that advanced age was a statistically significant predictor of an unfavorable 1-year functional outcome. In a receiver operating characteristic curve analysis for age, a patient age >58 years was determined as an appropriate cut-off value for predicting an unfavorable outcome. The patients aged >58 years showed an 82% positive predictive value (PPV) for an unfavorable outcome with mRS ≥4, and a 50% PPV for mRS ≥5. Moreover, a patient age cutoff value of >67 years exhibited a 100% PPV for predicting an unfavorable functional outcome with mRS ≥4. CONCLUSIONS: Advanced age was identified as a significant predictor of an unfavorable outcome and functional dependency. The PPV of a patient age >58 years and >67 years for predicting an unfavorable outcome with functional dependency was 82% and 100%, respectively.

Evaluation of a Pharmacokinetic Interaction between Telmisartan and Chlorthalidone in Healthy Male Adult Subjects.

BACKGROUND AND OBJECTIVE: Combination therapy is recommended for the effective management of hypertension according to most treatment guidelines, including those of the US Joint National Committee. Therefore, pharmacokinetic drug interactions are an important issue in combination therapy for hypertension. In this study, the pharmacokinetic properties of telmisartan and chlorthalidone were evaluated to investigate their pharmacokinetic interactions in healthy subjects. METHODS: Two separate, randomized, multiple-dose, two-period, one-sequence studies were conducted. In study A, 43 participants received 80 mg of telmisartan orally for 7 days, and were then administered oral chlorthalidone 25 mg for 14 days (days 8-21), coadministered with 80 mg of telmisartan from day 15. In study B, 14 participants received oral chlorthalidone (25 mg) for 13 days, followed by coadministration with 80 mg of telmisartan orally for 7 days. RESULTS: The geometric mean ratios (GMRs) (90 % confidence intervals [CIs]) of the maximum plasma concentration (C max,ss) and area under the concentration-time curve for the dosing interval at steady state (AUCτ,ss) of telmisartan (with and without chlorthalidone) were 1.018 (0.861-1.203) and 1.099 (1.015-1.190), respectively. For chlorthalidone (with/without telmisartan), the GMRs (90 % CIs) for C max,ss and AUCτ,ss were 0.996 (0.922-1.075) and 0.992 (0.925-1.064), respectively. The GMRs and 90 % CIs for telmisartan and chlorthalidone were all within the 0.80-1.25 range. CONCLUSION: Thus, in this study, there was no significant pharmacokinetic interaction between telmisartan and chlorthalidone. CLINICALTRIAL. GOV IDENTIFIER: NCT01806363.

Calvarial slope affecting accuracy of Ghajar Guide technique for ventricular catheter placement.

OBJECT The Ghajar Guide technique is used to direct a ventricular catheter at a 90° angle to the skull surface at Kocher's point. However, the human calvaria is not completely spherical. Lateral to the sagittal midline, the calvaria slopes downward with individual variation and thereby affects the accuracy of ventricular catheter placement. Accordingly, the authors investigated the accuracy of the orthogonal catheter trajectory using radiographic simulation and examined the effect of the calvarial slope on this accuracy. METHODS A catheter trajectory orthogonal to the skull surface at Kocher's point and the ideal catheter trajectory to the foramen of Monro were drawn bilaterally on coronal head images of 52 patients with hydrocephalus. The correction angle, the difference between the 2 catheter trajectories, was then measured. Meanwhile, the calvarial slope was measured around Kocher's point by using a coronal head image. The correlation between the correction angle and factors such as the calvarial slope and bicaudate index was then assessed using a Pearson correlation analysis. RESULTS The ventricular catheter trajectory orthogonal to the skull at Kocher's point in the patients with hydrocephalus led to a catheter trajectory into the ipsilateral (70.2%) or contralateral (29.8%) lateral ventricles. The correction angles ranged from -3.3° to 16.4° (mean ± SD 5.7° ± 3.7°). In 87 (83.7%) head sides, lateral deviation from the orthogonal trajectory was required to approximate the ideal trajectory, and the correction angle ranged from 2.0° to 16.4° (mean 6.7° ± 2.9°). The calvarial slope in the 104 head sides ranged from 15.6° to 32.5° (mean 24.2° ± 3.1°). Pearson correlation analysis revealed a strong positive correlation (r = 0.733) between the calvarial slope and the correction angle. CONCLUSIONS The accuracy of ventricular catheter placement using the Ghajar Guide technique is affected primarily by the calvarial slope around Kocher's point. A radiographic analysis of a preoperative coronal head image can be used to estimate the accuracy of ventricular catheter placement and enable adjustment to approximate the ideal catheter trajectory.

Height of aneurysm neck and estimated extent of brain retraction: powerful predictors of olfactory dysfunction after surgery for unruptured anterior communicating artery aneurysms.

OBJECTIVE: The highest incidence of olfactory dysfunction following a pterional approach and its modifications for an intracranial aneurysm has been reported in cases of anterior communicating artery (ACoA) aneurysms. The radiological characteristics of unruptured ACoA aneurysms affecting the extent of retraction of the frontal lobe and olfactory nerve were investigated as risk factors for postoperative olfactory dysfunction. METHODS: A total of 102 patients who underwent a pterional or superciliary keyhole approach to clip an unruptured ACoA aneurysm from 2006 to 2013 were included in this study. Those patients who complained of permanent olfactory dysfunction after their aneurysm surgery, during a postoperative office visit or a telephone interview, were invited to undergo an olfactory test, the Korean version of the Sniffin' Sticks test. In addition, the angiographic characteristics of ACoA aneurysms, including the maximum diameter, the projecting direction of the aneurysm, and the height of the neck of the aneurysm, were all recorded based on digital subtraction angiography and sagittal brain images reconstructed using CT angiography. Furthermore, the extent of the brain retraction was estimated based on the height of the ACoA aneurysm neck. RESULTS: Eleven patients (10.8%) exhibited objective olfactory dysfunction in the Sniffin' Sticks test, among whom 9 were anosmic and 2 were hyposmic. Univariate and multivariate analyses revealed that the direction of the ACoA aneurysm, ACoA aneurysm neck height, and estimated extent of brain retraction were statistically significant risk factors for postoperative olfactory dysfunction. Based on a receiver operating characteristic (ROC) analysis, an ACoA aneurysm neck height > 9 mm and estimated brain retraction > 12 mm were chosen as the optimal cutoff values for differentiating anosmic/hyposmic from normosmic patients. The values for the area under the ROC curves were 0.939 and 0.961, respectively. CONCLUSIONS: In cases of unruptured ACoA aneurysm surgery, the height of the aneurysm neck and the estimated extent of brain retraction were both found to be powerful predictors of the occurrence of postoperative olfactory dysfunction.

Comparative Cost Analysis for Surgical and Endovascular Treatment of Unruptured Intracranial Aneurysms in South Korea.

OBJECTIVE: A cost comparison of the surgical clipping and endovascular coiling of unruptured intracranial aneurysms (UIAs), and the identification of the principal cost determinants of these treatments. METHODS: This study conducted a retrospective review of data from a series of patients who underwent surgical clipping or endovascular coiling of UIAs between January 2011 and May 2014. The medical records, radiological data, and hospital cost data were all examined. RESULTS: When comparing the total hospital costs for surgical clipping of a single UIA (n=188) and endovascular coiling of a single UIA (n=188), surgical treatment [mean±standard deviation (SD) : ₩8,280,000±1,490,000] resulted in significantly lower total hospital costs than endovascular treatment (mean±SD : ₩11,700,000±3,050,000, p<0.001). In a multi regression analysis, the factors significantly associated with the total hospital costs for endovascular treatment were the aneurysm diameter (p<0.001) and patient age (p=0.014). For the endovascular group, a Pearson correlation analysis revealed a strong positive correlation (r=0.77) between the aneurysm diameter and the total hospital costs, while a simple linear regression provided the equation, y (₩)=6,658,630+855,250x (mm), where y represents the total hospital costs and x is the aneurysm diameter. CONCLUSION: In South Korea, the total hospital costs for the surgical clipping of UIAs were found to be lower than those for endovascular coiling when the surgical results were favorable without significant complications. Plus, a strong positive correlation was noted between an increase in the aneurysm diameter and a dramatic increase in the costs of endovascular coiling.

Bioequivalence of a single 400-mg dose of imatinib 100-mg oral tablets and a 400-mg tablet in healthy adult Korean volunteers.

BACKGROUND: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. A new once-daily 400-mg film-coated tablet of imatinib has been developed by a pharmaceutical company in Korea. OBJECTIVE: The present study was designed to assess and compare the PK parameters, bioavailability, and bioequivalence of the new imatinib 400-mg formulation (test) versus the conventional 100-mg formulation (reference) administered as a single 400-mg dose in healthy adult male volunteers. METHODS: This randomized, open-label, single-dose, two-way crossover study was conducted in healthy Korean male volunteers. Eligible subjects were randomly assigned in a 1 : 1 ratio to receive 400 mg of the test (one 400-mg tablet) or reference (four 100-mg tablets) formulation, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration. Plasma imatinib concentrations were determined using liquid chromatography coupled with tandem mass spectrometry. The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) of the adjusted geometric mean ratios for Cmax, AUC(0-t), and AUC(0-∞)ž were within the predetermined range of 0.80 - 1.25. RESULTS: In total, 35 subjects completed the study. No serious adverse event was reported during the study. The 90% CIs of the adjusted geometric mean ratios of the test formulation to the reference formulation for C(max), AUC(0-t) and AUC(0-∞)ž of imatinib were all within the bioequivalence criteria range of 0.8 - 1.25. CONCLUSIONS: The test formulation of imatinib met the Korean regulatory requirements for bioequivalence. Both imatinib formulations were well-tolerated in all subjects.

Population pharmacokinetic and pharmacodynamic modeling of transformed binary effect data of triflusal in healthy Korean male volunteers: a randomized, open-label, multiple dose, crossover study.

BACKGROUND: Triflusal is a drug that inhibits platelet aggregation. In this study we investigated the dose-exposure-response relationship of a triflusal formulation by population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of its main active metabolite, hydroxy-4-(trifluoromethyl) benzoic acid (HTB). METHODS: This study was a randomized, open-label, multiple-dose, two-period, two-treatment, comparative crossover design. All volunteers received a single oral loading dose of 900 mg of triflusal on Day 1, followed by a dose of 600 mg/day from Day 2 to 9. Using data from 34 healthy volunteers, 476 HTB plasma concentration data points and 340 platelet aggregation data points were used to construct PK and PD models respectively using NONMEM (version 6.2). As the PD endpoint was qualitative, we implemented binary analysis of 'inhibition' and 'non-inhibition' rather than using the actual value of the test. The final PK-PD model was evaluated using a visual predictive check (VPC) and bootstrap. RESULTS: The time-concentration profile of HTB over the entire dosing period was described by a one-compartment model with a first-order formation rate constant for HTB. Weight was selected as a covariate for clearance and volume of triflusal, respectively. The structure and the population estimates for triflusal PK were as follows: oral clearance (CL/F) = 0.2 · (weight/71.65)(0.845) L/h, oral volume of distribution (V/F) = 8.3 · (weight/71.65) L, and k f = 0.341 h(-1). A sigmoid relationship between triflusal concentration and the probability of significant inhibition with shape factor was chosen as the final PD model. No time delay between concentration and response was identified. The final structure between predicted concentration (C(y)(pred,ij) and the probability of inhibition of platelet aggregation (IPA) relationship was as follows: Probability of IPA = C(19)(pred,ij)/((84.9)(19) µg/mL + C(19)(pred,ij)). Thus, we concluded this relationship is more like quantal concentration-response relationship. The current dosing regimen was considered to be efficacious based on the EC 50 estimate of 84.9 µg/mL obtained in this study. CONCLUSIONS: A PK and binary probability PD model of triflusal was successfully developed for Korean healthy volunteers. The model may be used to further prediction inhibition of platelet aggregation by triflusal. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0001299 (Registered December 5, 2014).

Efficacy of Dual Energy X-ray Absorptiometry for Evaluation of Biomechanical Properties: Bone Mineral Density and Actual Bone Strength.

INTRODUCTION: Bone mineral density (BMD) is an important index in diagnosis of osteoporosis and other metabolic bone diseases, prediction of fractures, and monitoring treatment. This study was to find a more feasible technique for prediction of osteoporotic fracture between dual energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and to reveal the actual change of bone strength when BMD was changed. METHODS: Ten of these 20 specimens were used as the demineralized group and the other 10 as the control. Each specimen was immersed in HCl solution at for a period of at least 10 minutes, up to 100 minutes, at an interval of 10 minutes for different levels of demineralization. BMD was measured using DXA and QCT. Uniaxial compression tests were conducted to measure biomechanical parameters. Pearson correlation analysis was used respectively between BMD and biomechanical parameters and between DXA and QCT. RESULTS: Elastic modulus (r=0.87) and yield stress (r=0.84) showed a statistically significant correlation with DXA BMD. Through correlation analysis with QCT BMD and elastic modulus, correlation coefficient showed hemi-vertebra (r=0.80) and trabecular (r=0.68). In yield stress, there was a statistically significant correlation in hemi-vertebra (r=0.87) and trabecular bone (r=0.84). CONCLUSION: DXA is a current standard technique not only for diagnosis of osteoporosis but also for prediction of fracture risk compared to QCT. Actual decrease of bone strength was much greater than that of BMD by both DXA and QCT.

Immunostimulatory effect of fermented red ginseng in the mouse model.

In this study, Woongjin fermented red ginseng extract (WFRG) was evaluated for its potential ability to act as an adjuvant for the immune response of mice. For the in vitro study, macrophages were treated with serial concentrations (1 µg/mL, 10 µg/mL, and 100 µg/mL) of WFRG. For in vivo studies, mice were administered different concentrations (10 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day) of WFRG orally for 21 days. In vitro, the production of nitric oxide and TNF-α by RAW 264.7 cells increased in a dose-dependent manner. In vivo, WFRG enhanced the proliferation of splenocytes induced by two mitogens (i.e., concanavalin A and lipopolysaccharide [LPS]) and increased LPS-induced production of TNF-α and IL-6, but not IL-1ß. In conclusion, WFRG has the potential to modulate immune function and should be further investigated as an immunostimulatory agent.

Rehab Games as Components of Workflow: A Case Study.

OBJECTIVE: This study explored and evaluated the integration of rehabilitation games into therapy workflow. MATERIALS AND METHODS: A multistage and multimethod study was followed: (1) A formative study involving observations and interviews with a total of approximately 90 therapists across the rehabilitation continuum was conducted for the design and development of an interactive therapy platform using Microsoft(®) (Redmond, WA) Kinect(®) for Windows. (2) A pilot study was carried out in an inpatient facility, involving patients and therapists. (3) Heuristic evaluation was performed on the basis of the principles of universal design. RESULTS: The findings from the study show the overall appeal of the system to patients and therapists, but also the challenges of integrating the system into the workflow. CONCLUSIONS: The findings from the study are in line with other similar studies in terms of the appeal and potential impact of games for rehabilitation and the applicability of the principles of universal design, as well as the need for institutional and public policy changes in the field of medical rehabilitation.

Influence of hepatic dysfunction on the pharmacokinetics and safety of fimasartan.

This study was designed to assess the pharmacokinetics (PK) and safety of fimasartan, an angiotensin II type 1 receptor blocker, in hepatic impairment patients as compared with healthy subjects. An open-label, single-dose, parallel study was conducted in 6 healthy male volunteers and 12 subjects with hepatic impairment. Healthy subjects were matched with hepatic dysfunction patients on the basis of age, gender, and body weight. After a single 120-mg oral administration of fimasartan, PK parameters and safety were analyzed between the hepatic dysfunction groups and healthy group. Compared with the healthy subjects, the geometric mean ratio and 90% confidence intervals for the maximum plasma concentration and the mean area under the plasma concentration-time curve from 0 to infinity (AUC)inf were 0.77 (0.24-2.47) and 1.11 (0.50-2.46), respectively, for the mild hepatic impairment and 6.55 (3.56-12.03) and 5.17 (4.19-6.37), respectively, for moderate hepatic impairment. However, there was no significant difference in time to peak plasma concentration (t(max)) and elimination half-life, and there were no serious or severe adverse events in all subjects. Subjects with mild hepatic impairment exhibited similar bioavailability compared with healthy subjects, whereas subjects with moderate hepatic impairment seemed to exhibit a higher level of systemic exposure to fimasartan than healthy subjects. In addition, all subjects were tolerable with fimasartan.

Rapid determination of sumatriptan in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetic study.

A sensitive and simple detection method coupling ultra-performance liquid chromatography with tandem mass spectrometry was developed and validated to analyze sumatriptan levels in human plasma. The plasma sample preparations for the analysis were based on liquid-liquid extraction with ethyl acetate, evaporation, and reconstitution. MS/MS detection was performed on a triple-quadrupole tandem mass spectrometer by monitoring the protonated parent→daughter ion pairs at m/z 296→58 and m/z 388→71 for sumatriptan and terazosin (internal standard), respectively. The method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear from 0.5 to 50 ng/mL (r>0.999). The mean extraction recovery for sumatriptan was higher than 62.3%. The method accuracy was within 97.4%, and the relative standard deviation of the intra- and inter-day precision values was within 11.7% at all quality control levels. Plasma samples that contained sumatriptan were stable under three freeze-thaw cycles, short- and long-term storage, and autosampler conditions. This method was successfully applied to a pharmacokinetic study conducted with 10 healthy volunteers. After oral administration of 50-mg sumatriptan and serial blood sampling over 12 h, the mean area under the plasma concentration-time curve from time 0 to 12 h and the maximum plasma concentration were 116.2 ng h/mL and 33.2 ng/mL, respectively.

High-throughput screening of inhibitory effects of Bo-yang-hwan-o-tang on human cytochrome P450 isoforms in vitro using UPLC/MS/MS.

Bo-yang-hwan-o-tang (BHT) is an oriental herbal medicine for treating brain disorders such as cerebral ischemia. The objective of this study was to develop an economically feasible and time-saving high-throughput screening method to monitor the potential inhibitory effects of BHT on human cytochrome P450 (CYP) enzymes in vitro. Two cocktail sets were used for incubation of human liver microsomes: Cocktail A: 6 probe substrates for CYP1A2, CYP2A6, CYP2C8, CYP2C19, CYP2D6, CYP3A4; Cocktail B: 3 for CYP2B6, CYP2C9, CYP2E1. The concentrations of the substrate metabolites were simultaneously analyzed using UPLC/MS/MS. The BHT extract had almost negligible inhibitory effects on the nine human CYP isoforms tested, with the half-maximal inhibitory concentration value ranged from 3624.99 to 45412.44 µg/ml. The results suggest that BHT extract has no inhibitory effects on CYP isoforms within the clinically recommended dosage range. We conclude that BHT might be free of drug-herb interactions when co-administered with other medicines. However, more in vivo human studies are needed to confirm these results. The high-throughput screening method can be a useful tool for drug discovery and for understanding drug interactions.

Quantile normalization approach for liquid chromatography-mass spectrometry-based metabolomic data from healthy human volunteers.

In metabolomic research, it is important to reduce systematic error in experimental conditions. To ensure that metabolomic data from different studies are comparable, it is necessary to remove unwanted systematic factors by data normalization. Several normalization methods are used for metabolomic data, but the best method has not yet been identified. In this study, to reduce variation from non-biological systematic errors, we applied 1-norm, 2-norm, and quantile normalization methods to liquid chromatography-mass spectrometry (LC-MS)-based metabolomic data from human urine samples after oral administration of cyclosporine (high- and low-dose) in healthy volunteers and compared the effectiveness of the three methods. The principal component analysis (PCA) score plot showed more obvious groupings according to the cyclosporine dose after quantile normalization than after the other two methods and prior to normalization. Quantile normalization is a simple and effective method to reduce non-biological systematic variation from human LC-MS-based metabolomic data, revealing the biological variance.

Single-dose pharmacokinetics and dose proportionality of intravenous pazufloxacin mesilate in healthy Korean volunteers.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and dose proportionality of a single, intravenous dose of pazufloxacin mesilate, an injectable fluoroquinolone antibiotic, in healthy Korean male volunteers. METHODS: In this open-label, four-dose, parallel study, subjects were randomized to receive a single dose of pazufloxacin mesilate 300, 500, 600, and 1,000 mg (n = 6, 20, 6, and 8, respectively) administered as a 1-h intravenous infusion. Blood and urine samples were collected serially from 0 to 24 h after drug administration and analyzed using a validated HPLC method. Tolerability was assessed by monitoring clinical laboratory parameters and adverse events. RESULTS: After single-dose intravenous administration of pazufloxacin mesilate, the mean C(max) for groups treated with 300, 500, 600, and 1,000 mg doses ranged from 5.11 to 18.06 µg/mL; the mean AUC(0-t) ranged from 13.70 to 58.60 µg × h/mL. Pazufloxacin exhibits Lack of dose proportionality was concluded over the dose range of 300 - 1,000 mg, based on linear regression model and power model . At all four dosages studied, pazufloxacin mesilate was well tolerated. CONCLUSIONS: Our data suggest that all regimens of pazufloxacin administration were well tolerated. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 - 1,000 mg.

Assessment of pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers.

OBJECTIVE: Levofloxacin and cyclosporine show different pharmacokinetic properties, but are known to be dose proportional within the therapeutic range. The authors evaluated the pharmacokinetic proportionality of levofloxacin and cyclosporine over a 100-fold dose range in healthy human volunteers, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: Two independent, randomized, crossover studies were performed. For levofloxacin, eight volunteers were randomly assigned in a 1:1 ratio to receive a low dose (7.5 mg) orally or intravenously, followed by a 1-week washout period and administration via the alternate route. After another 1-week washout period, a therapeutic dose (750 mg) was administered to all eight subjects. For cyclosporine, another eight volunteers received a low dose (2 mg) or a therapeutic dose (200 mg) orally with a 1-week washout period. Drug concentrations were determined by LC-MS/MS. RESULTS: For levofloxacin, the mean values for dose-normalized C(max) and AUC(last) with the two doses were as follows: therapeutic dose, 15.2 ± 4.6 ng/ml/mg and 103.6 ± 15.5 ng·h/ml/mg, respectively; low dose, 17.1 ± 6.5 ng/ml/mg and 72.6 ± 8.7 ng·h/ml/mg, respectively. For cyclosporine, the mean values for dose-normalized C(max) and AUC(last) were as follows: therapeutic dose, 4.9 ± 1.5 ng/ml/mg and 15.4 ± 4.9 ng·h/ml/mg, respectively; low dose, 1.6 ± 0.6 ng/ml/mg and 9.3 ± 7.3 ng·h/ml/mg, respectively. CONCLUSION: In this study levofloxacin, which is completely absorbed and primarily eliminated renally without modification, showed better pharmacokinetic proportionality than cyclosporine, which is poorly absorbed and extensively metabolized.