Choon Ok Kim

Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers.

AIM The organic cation transporter 1 (OCT1) plays a key role in the cellular transport of metformin and its subsequent glucose-lowering effect. A recent non-clinical study reported that metformin uptake into hepatocytes is regulated via OCT1, and that uptake was strongly inhibited by verapamil. Therefore, we investigated the effects of verapamil co-administration on the pharmacokinetics and pharmacodynamics of metformin in humans. METHODS We evaluated the pharmacokinetics and the anti-hyperglycaemic effects of metformin using an oral glucose tolerance test (OGTT) in 12 healthy participants, before (day 1) and after metformin treatment (day 2), and again on days 15 and 16 after co-administration with verapamil. RESULTS Verapamil inhibited the ability of metformin to reduce maximum blood glucose concentrations (ΔGmax ) by 62.5% (P = 0.008) and decreased the area under the glucose concentration-time curve (ΔAUCgluc ) by 238% (P = 0.015). However, verapamil did not significantly alter the Cmax and the AUC of metformin, nor its renal clearance. CONCLUSIONS Our results suggest that verapamil remarkably decreases the glucose-lowering effect of metformin, possibly by acting as a competitive inhibitor of OCT1.

Clinical Predictors of Novel Influenza A (H1N1) Infection in Korea

Purpose Pandemic influenza A (H1N1) virus has spread rapidly and prompt diagnosis is needed for successful treatment and prevention of transmission. We investigated clinical predictors, validated the use of previous criteria with laboratory tests, and evaluated the clinical criteria for H1N1 infection in the Korean population. Materials and Methods We analyzed clinical and laboratory evaluation data from outpatient clinics at Severance Hospital in Seoul, Korea between November 11 and December 5, 2009. Results This analysis included a total of 828 patients. Of these, 372 (44.9%) patients were confirmed with H1N1 infection by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The most common and predictive symptom was cough (90.3%, OR 8.87, 95% CI 5.89-13.38) and about 40% of H1N1-positive patients were afebrile. The best predictive model of H1N1 infection was cough plus fever or myalgia. The sensitivities, specificities, positive predictive values, and negative predictive values of our suggested criteria were 73.9%, 69.5%, 66.4%, and 76.6%, respectively. Conclusion Cough was the most common independent symptom in patients with laboratory-confirmed H1N1 infection, and while not perfect, the combination of cough plus fever or myalgia is suggested as clinical diagnostic criteria. Health care providers in Korea should suspect a cough without fever to be an early symptom of H1N1 infection.

Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics.

Objective Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin. Methods We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics. Results Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.−130G>A and haplotype 2 containing two polymorphisms, g.−609G>A and g.−396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539±76 (reference group) vs. 633±102 (variant group) ml/min; P=0.006] and secretion clearance [439±81 (reference group) vs. 531±102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group. Conclusion Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.

Influence of ABCC2, SLCO1B1, and ABCG2 polymorphisms on the pharmacokinetics of olmesartan.

Abstract: This study was designed to determine whether genetic polymorphisms of multidrug-resistant protein 2 (ABCC2), organic anion transporting polypeptide 1B1 (SLCO1B1), and breast cancer resistance protein (ABCG2) have an effect on olmesartan pharmacokinetics in Korean subjects. Sixty-eight healthy male volunteers who participated in previous pharmacokinetics studies of olmesartan medoxomil (single dose, 20 mg or 40 mg) were enrolled. All subjects were analyzed and grouped according to the genotypes of ABCC2, SLCO1B1, and ABCG2. The dose-normalized peak plasma concentration (Cmax) and area under the plasma concentration–time curve (AUCt) values were analyzed. The dose-normalized mean Cmax and AUCt in the ABCC2 -24CT genotype group were higher than those in the -24CC genotype group [Cmax,dn: CT 26.1 ± 6.5 (ng/mL)/mg versus CC 22.1 ± 6.7 (ng/mL)/mg, P = 0.010, AUCt,dn: CT 178.7 ± 45.6 (hr·ng−1·mL−1)/mg versus CC 149.9 ± 39.8 (hr·ng−1·mL−1)/mg, P = 0.010]. The difference in AUCt,dn between the ABCC2 -1549GG and -1549GA genotype groups was statistically significant [GG 149.0 ± 41.0 (hr·ng−1·mL−1)/mg versus. GA 174.1 ± 43.3 (hr·ng−1·mL−1)/mg, P = 0.019]. No significant differences were observed for any other single nucleotide polymorphism in ABCC2, SLCO1B1, or ABCG2. The ABCC2 -24CC genotype group exhibited lower systemic exposure of olmesartan than the -24CT genotype group, whereas no significant differences were observed in the other transporter genotype groups.

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

Abstract: 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 (tmax) 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.

Relationship Between Earlobe Crease and Brachial-ankle Pulse Wave Velocity in Non-hypertensive, Non-diabetic Adults in Korea

OBJECTIVES Several studies have found a significant association between the presence of earlobe crease (ELC) and cardiovascular disease (CVD). Brachial-ankle Pulse Wave Velocity (baPWV) is a non-invasive and useful measure of arterial stiffness predicting cardiovascular events and mortality. However, few studies have reported the relationship between ELC and baPWV as a new measure of arterial stiffness. The purpose of this study was to determine whether ELC is related to baPWV in non-diabetic, non-hypertensive, and apparently healthy Korean adults. METHODS A cross-sectional study was conducted on 573 non-hypertensive, non-diabetic Korean adults aged 20-80 yr. Subjects were stratified into three groups according to gender and menopausal status. baPWV was measured by an automatic waveform analyser. The association between ELC and baPWV was assessed by multiple linear regression analysis after adjusting for conventional cardiovascular disease risk factors including age, gender, blood pressure, lipid profile, and smoking status etc. RESULTS The overall frequency of ELC was 19.02% and the subjects with ELC showed significantly higher mean baPWV (p<0.0001). Multiple linear regression of subjects revealed that the presence of ELC was independently associated with baPWV (male, p<0.0001; premenopausal female p=0.0162; postmenopausal female p=0.0208). CONCLUSION ELC had a significant correlation with baPWV, independently controlling for other classical cardiovascular risk factors in adults aged 20 yr or older. ELC is an important surrogate marker of increased arterial stiffness as measured by baPWV in Korean adults.

Is abdominal obesity associated with the 2009 influenza A (H1N1) pandemic in Korean school-aged children?

Please cite this paper as: Kim et al. (2012) Is abdominal obesity associated with the 2009 influenza A (H1N1) pandemic in Korean school‐aged children? Influenza and Other Respiratory Viruses 6(5), 313–317.

Comparison of Pharmacokinetics and Safety of a Fixed-dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects

PURPOSE Rosuvastatin and ezetimibe are concomitantly used for dyslipidemia treatment. Compared with separate tablets, fixed-dose combination (FDC) tablets of rosuvastatin/ezetimibe could increase patient compliance. The aim of this study was to compare the pharmacokinetic (PK) profiles of an FDC tablet of rosuvastatin/ezetimibe and co-administration of rosuvastatin and ezetimibe as separate tablets in healthy Korean volunteers. METHODS This trial was a randomized, open-label, single-dose, 2-way crossover study. The healthy subjects received an FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg (test) or co-administration of rosuvastatin 20 mg and ezetimibe 10 mg (reference) in each period (periods 1 and 2), with a 14-day washout period. The blood samples for PK analysis were collected predose and up to 96 hours after administration, and safety was assessed throughout the study. FINDINGS Sixty-four healthy Korean subjects were enrolled, and 57 subjects completed the study. All subjects were men and mean age was 28.52 ± 5.93. The geometric least squares mean ratios (test/reference) and 90% CIs of Cmax and AUC0-last were 101.54% (94.03-109.65) and 97.71% (91.86-103.93) for rosuvastatin, 108.93% (98.55-120.40) and 102.90% (96.72-109.47) for free ezetimibe, and 106.74% (98.18-116.05) and 104.24 % (99.53-109.17) for total ezetimibe. Twenty-four adverse events (AEs) were reported in 22 subjects. Three cases were related to the study drugs; 2 cases were mild, and 1 case was severe. However, all AEs were resolved without any sequelae. In addition, there were no serious AEs throughout the study. IMPLICATIONS The FDC tablet of rosuvastatin/ezetimibe was well tolerated and resulted in comparable systemic exposure with co-administration of rosuvastatin and ezetimibe. ClinicalTrials.gov identifier: NCT02941848.

Effects of clarithromycin on the pharmacokinetics of evogliptin in healthy volunteers

Evogliptin (DA‐1229), a novel dipeptidyl peptidase (DPP)‐4 inhibitor with high potency and selectivity, was approved in Korea for the treatment of type 2 diabetes. Preclinical studies suggest that it is metabolized by cytochrome (CYP) P450 isozymes. Based on these findings, a clinical study was designed to investigate the pharmacokinetic (PK) interaction of evogliptin with a CYP inhibitor, clarithromycin.

Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?

To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration–time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism.