Young-Ran Yoon

Effects of Cyp2c19 and Cyp2c9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans

Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9*1 genotype; the other six subjects were of the CYP2C9*1/*3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9*3 allele, C(max) and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9*1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9*1/*3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9*3 subjects (P < 0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.

Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects

To evaluate the relationship between the metabolic ratio (MR) of metoprolol, CYP2D6*10B genotype, and the disposition of paroxetine in Korean subjects.

An Integrative Approach for Identifying a Metabolic Phenotype Predictive of Individualized Pharmacokinetics of Tacrolimus

Individual variation in drug response is influenced by both genes and environment. We evaluated the potential of a metabolic phenotype to predict individual variation in the pharmacokinetics (PK) of tacrolimus. Liquid chromatography–mass spectroscopy (LC‐MS)‐based metabolic profiling was performed on 29 healthy volunteers by measuring the levels of 1,256 metabolite ions in their predose urine samples. After oral administration of tacrolimus, we monitored its plasma concentrations in these volunteers for up to 72 h and calculated the pharmacokinetic parameters. Partial least‐squares (PLS) modeling was conducted with data relating to predose urine metabolites to predict the pharmacokinetic parameters of tacrolimus and to select the metabolites that substantially contributed to such prediction. The selection of these metabolites allowed us to understand their functional role and generate a clinically applicable index to predict individualized PK of tacrolimus. In conclusion, this integrative pharmacometabolomic approach, combining the metabolic profiling of predose urine with PLS modeling, can serve as a useful tool in “individualized drug therapy.”

Bioequivalence and tolerability of two clopidogrel salt preparations, besylate and bisulfate: a randomized, open-label, crossover study in healthy Korean male subjects.

BACKGROUND Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients. OBJECTIVE The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval. METHODS A randomized, open-label, 2-period, single- and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-mumol/L adenosine diphosphate was measured using turbidometric aggregometry during the single- and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis. RESULTS Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for C(max), T(max), and AUC(0-t) with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for Cmax, AUC(0-t), and AUC(0-infinity) with the SR26334 of clopidogrel besylate (10.9 microg/mL, 38.8 microg/mL/h, and 43.0 microg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 microg/mL, 40.6 microg/mL/h, and 43.8 microg/mL/h). The mean values for maximal antiplatelet effect (Emax) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h . % and 4299.1 h . % inhibition, respectively; and clopidogrel bisulfate, 61.7 h . % and 4406.9 h . % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed C(max), AUC, E(max), and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocytopenia (1 subject [2.3%] in the group receiving the clopidogrel bisulfate). All adverse events were transient and mild. CONCLUSIONS In these healthy Korean male subjects, the differences in the pharmacokinetic and pharmacodynamic properties between the 2 clopidogrel salt preparations did not reach statistical significance and met the regulatory requirements for bioequivalence. Both preparations were well tolerated.

Revival of TE2A; a better chelate for Cu(II) ions than TETA?

A highly effective synthetic route for TE2A was developed and the (64)Cu-labeled TE2A complexes showed higher kinetic inertness and faster clearance than most commonly used TETA analogs.

MDR1 genetic polymorphisms and comparison of MDR1 haplotype profiles in Korean and vietnamese populations

Two representative genetic variants of the MDR1 gene, 3435C>T and 2677G>T/A, show wide interethnic differences in its genetic polymorphism. In this study, the authors evaluated the genetic polymorphisms of MDR1 and directly compared MDR1 haplotype profiles of the Korean and Vietnamese populations. The 3435C>T and 2677G>T/A variations were analyzed in 632 Koreans and 142 Vietnamese using pyrosequencing. The allelic frequencies of 3435C>T did not significantly differ between the Korean (39.3%) and Vietnamese (36.6%) groups. However, the frequencies of mutant alleles at 2677 locus (T or A allele) showed a significant difference between Koreans (56.2%) and Vietnamese (41.9%), as the frequency of 2677A allele in the Korean subjects (17.1%) was much higher than that of the Vietnamese subjects (6.3%). Linkage analysis revealed that 2677A allele is closely linked to 3435C allele. The frequency of 2677A-3435C haplotype in Koreans was 15.4%, which was significantly higher than that found in Vietnamese subjects (6.3%). In conclusion, the frequencies of MDR1 variants and haplotype profiles showed significant differences between the Korean and Vietnamese populations, especially with respect to the 2677G>T/A variants. Because the 2677A allele was recently found to be functional in vivo and was detected at a high frequency in Koreans, the genotyping of this variant is necessary for pharmacogenetic studies of MDR1 in this population. In addition, by virtue of strong linkage disequilibrium, 2677A-3435C haplotype may help improve the predictability of MDR1 genetic polymorphism for MDR1 functional changes.

Pattern Recognition Analysis for Hepatotoxicity Induced by Acetaminophen Using Plasma and Urinary 1H NMR-Based Metabolomics in Humans

Drug-induced liver injury (DILI) is currently an increasingly relevant health issue. However, available biomarkers do not reliably detect or quantify DILI risk. Therefore, the purpose of this study was to comparatively evaluate plasma and urinary biomarkers obtained from humans treated with acetaminophen (APAP) using a metabolomics approach and a proton nuclear magnetic resonance (NMR) platform. APAP (3 g/day, two 500 mg tablets every 8 h) was administered to 20 healthy Korean males (age, 20-29 years) for 7 days. Urine was collected daily before and during dosing and 6 days after the final dose. NMR spectra of these urine samples were analyzed using principal component analysis (PCA) and partial least-squares-discrimination analysis. Although the activities of aspartate aminotransferase and lactate dehydrogenase were significantly increased 7 days post-APAP treatment, serum biochemical parameters of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, γ-glutamyl transpeptidase, and lactate dehydrogenase were within normal range of hepatic function. However, urine and plasma (1)H NMR spectroscopy revealed different clustering between predosing and after APAP treatment for global metabolomic profiling through PCA. Urinary endogenous metabolites of trimethylamine-N-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, hippurate, and glutarate as well as plasma endogenous metabolites such as lactate, glucose, 3-hydroxyisovalerate, isoleucine, acetylglycine, acetone, acetate, glutamine, ethanol, and isobutyrate responded significantly to APAP dosing in humans. Urinary and plasma endogenous metabolites were more sensitive than serum biochemical parameters. These results might be applied to predict or screen potential hepatotoxicity caused by other drugs using urinary and plasma (1)H NMR analyses.

Effect of rifampin on the plasma concentration and the clinical effect of haloperidol concomitantly administered to schizophrenic patients.

We assessed the changes of plasma haloperidol concentrations and clinical responses repeatedly up to 4 weeks after coadministration or discontinuation of rifampin in 12 schizophrenic patients taking haloperidol alone (group I) and 5 patients taking haloperidol and antituberculotic drugs (group II). After coadministration of rifampin in group I, daily trough haloperidol concentrations rapidly decreased and reached 63% of baseline level by day 3, 41.3% by day 7, and 30% by day 28. On the other hand, after discontinuation of rifampin in group II, plasma haloperidol concentration increased to 140.7% of baseline level by day 3, 228.7% by day 7, and 329% by day 28. In this study, a 30% or greater change in the clinical rating scale was considered a positive clinical response of the drug interaction. Using this criterion, 50% of the group I subjects responded according to the Brief Psychiatric Rating Scale (BPRS) total score, and 25% responded according to the BPRS subscale for psychiatric symptoms. No positive responses were observed in group II patients. These results strongly suggest that rifampin interacts with the clinical effects as well as the plasma concentrations of coadministered haloperidol, and careful monitoring should be considered when coadministration or discontinuation of rifampin is needed in a schizophrenic patient taking haloperidol.

Effect of age on the pharmacokinetics of fimasartan (BR-A-657)

Objectives: The aim of this study was to compare the pharmacokinetics (PK) and safety of fimasartan (BR-A-657), an angiotensin II receptor antagonist, between healthy young (19 – 45 years) and older (≥ 65 years) male subjects. Methods: To assess the effect of age on PK and safety, fimasartan was administered as a single 240 mg tablet to 12 young and 10 older male subjects, followed by serial blood sampling over 48 h. Plasma concentrations of fimasartan were analyzed using validated HPLC-MS/MS. Clinical and laboratory adverse events were assessed. Results: After oral administration of 240 mg fimasartan, the mean area under the plasma concentration-time curve from time zero to infinity (AUC0→∞) was 2899.0 ng/ml/h in the older, which was significantly greater than in young subjects (1767.4 ng/ml/h; p = 0.03). The geometric mean AUC0→∞ was 69.4% higher in older than in young subjects. The maximum plasma concentration (Cmax), time to reach Cmax and elimination half-life for fimasartan did not differ significantly between the older and young groups. Importantly, fimasartan was well tolerated during this study. Conclusions: While some PK parameters were statistically different between the two groups, the effect of age on the PK was modest (e.g., AUC increase < twofold in older subjects).

Frequency of CYP2C9 variant alleles, including CYP2C9*13 in a Korean population and effect on glimepiride pharmacokinetics

What is known and Objective:  Cytochrome P450 (CYP) 2C9 is a clinically important enzyme involved in the metabolism of many drugs commonly used in humans. Of several allelic variants known to affect the catalytic activity of the CYP2C9 enzyme, the frequencies of the CYP2C9*3 and CYP2C9*13 alleles in the Korean population have been reported as 1·1% and 0·6%, respectively. Our objective was to re‐evaluate the frequencies of CYP2C9 allelic variants in the Korean population, including the CYP2C9*13 allele by pyrosequencing, and to investigate the pharmacokinetics of glimepiride in relation to CYP2C9 genotypes, including CYP2C9*3/*3.