Pomegranate juice does not affect the disposition of simvastatin in healthy subjects.

Previous in vitro and in vivo investigations reported controversial results for the inhibitory potential of pomegranate on Cytochrome P450 (CYP) 3A activity. This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic parameters of simvastatin and simvastatin acid were compared among the study periods. In the period of grapefruit juice, the mean C max and AUCinf of simvastatin [the geometric mean ratio (90 % CI) 15.6 (11.6-21.0) and 9.1 (6.0-13.7)] were increased significantly when compared with the control period, whereas they were not significantly different in the period of pomegranate juice [C max and AUCinf 1.20 (0.89-1.62) and 1.29 (0.85-1.94)]. The mean C max and AUCinf of simvastatin acid were increased significantly after intake of grapefruit juice, but not pomegranate juice. These results suggest that pomegranate juice affects little on the disposition of simvastatin in humans. Pomegranate juice does not seem to have a clinically relevant inhibitory potential on CYP3A4 activity.

Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin.

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5-111.0) and 107.1 (100.1-114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.

Effect of voglibose on the pharmacokinetics of metformin in healthy Korean subjects.

OBJECTIVE: The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. METHODS: A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. RESULTS: 22 subjects completed the study. The geometric mean ratios for C(ss,max) of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUC-τ, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). CONCLUSIONS: Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects.

AIMS: The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol. METHODS: A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol) were measured using liquid chromatography-tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment. RESULTS: The geometric mean ratios of area under the concentration-time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89-1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90-1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93-1.03; P = 0.47) for 4'-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments. CONCLUSIONS: Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.

CYP2C19 poor metabolizer is associated with clinical outcome of clopidogrel therapy in acute myocardial infarction but not stable angina.

BACKGROUND: More intensive platelet suppression is required in patients with acute myocardial infarction (AMI) than in those with stable angina because of differential platelet activation between AMI and stable angina. In this context, CYP2C19 genotype leading to reduced active metabolite formation may profoundly affect the clinical outcome of clopidogrel therapy in patients with AMI compared with those with stable angina. METHODS AND RESULTS: Effects of CYP2C19 genotypes on the clinical outcome of clopidogrel therapy were evaluated in 2188 patients (532 patients with AMI and 1656 patients with stable angina) undergoing percutaneous coronary intervention. The primary clinical outcome was a composite of major adverse cardiac and cerebrovascular events defined as death from any cause, nonfatal myocardial infarction, or stroke during 1 year of clopidogrel therapy. Compared with extensive metabolizer, the CYP2C19 poor metabolizer was significantly associated with higher risk of major adverse cardiac and cerebrovascular events in patients with AMI (hazard ratio, 2.88; 95% confidence interval, 1.27-6.53; P=0.011). However, this finding was not seen in patients with stable angina. A significant interaction between CYP2C19 genotypes and disease subsets of AMI and stable angina was identified with respect to major adverse cardiac and cerebrovascular events (adjusted interaction P=0.045). The patients with AMI showed lower percent inhibition of P2Y12 compared with patients with stable angina in CYP2C19 poor metabolizer or CYP2C19 intermediate metabolizer genotype groups but not in CYP2C19 extensive metabolizer genotype group. CONCLUSIONS: CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina. CLINICAL TRIAL REGISTRATION INFORMATION: URL: clinicaltrials.gov. Identifier: NCTO1239914.

High-sensitive LC-MS/MS method for the simultaneous determination of mirodenafil and its major metabolite, SK-3541, in human plasma: application to microdose clinical trials of mirodenafil.

A high-sensitivity LC/MS/MS method was developed and validated for the simultaneous determination of mirodenafil and its major metabolite, SK-3541, in human plasma. Mirodenafil, SK-3541, and udenafil as an internal standard were extracted from plasma samples with methyl tert-butyl ether. Chromatographic separation was performed on a Luna phenyl-hexyl column (100 × 2.0 mm) with an isocratic mobile phase consisting of 5 mM ammonium formate and ACN (23:77, v/v) at a flow rate of 0.35 mL/min. Detection and quantification were performed using a mass spectrometer in selected reaction monitoring mode with positive ESI at m/z 532.3 → 296.1 for mirodenafil, m/z 488.1 → 296.1 for SK-3541, and m/z 517.3 → 283.2 for udenafil. The calibration curves were linear over a concentration range of 2-500 pg/mL using 0.5 mL plasma for the microdose of mirodenafil (100 µg). Analytical method validation of the clinical dose (100 mg), with a calibration curve range of 2-500 ng/mL using 0.025-mL plasma, was also conducted. The other LC-MS/MS conditions were similar to those used for the microdosing. Each method was applied successfully to pharmacokinetic studies after a microdose or clinical dose of mirodenafil to six healthy Korean male volunteers.

Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects.

In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers. Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively. The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P < .001 and P < .001, respectively) but not during the clarithromycin phase (P = .099 and P = .090, respectively). Exposure to sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes. These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo.

Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals.

Hepatocyte nuclear receptor 4α (HNF4α) plays a central role in regulating human drug-metabolizing enzymes. Our previous study suggested that the newly identified polymorphism G60D in the HNF4α gene may decrease its downstream CYP2D6 activity in Asians. To confirm this effect in a clinical setting, we carried out a full pharmacokinetic study of a single oral dose of CYP2D6 substrate tolterodine in 30 healthy Korean individuals (HNF4α wild type: n = 24; HNF4α G60D heterozygotes: n = 6) who were pregenotyped for CYP2D6. Our study showed HNF4α G60D to be an independent predictor for increased AUC0-∞, C max of tolterodine and increased AUC0-∞ of the active moiety (tolterodine+5-hydroxymethyl-tolterodine) (P<0.05). A significant proportion of the variance in these parameters (R = 0.81, 0.59, and 0.63, respectively; P<0.01) was explained together by CYP2D6 and HNF4α genotypes. Further investigation of HNF4α genetic polymorphisms may improve the predictability of CYP2D6 activity in different populations.

Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index.

AIMS: To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the CYP2B6*6 genotype and explore potential phenotyping indices for CYP2B6 activity in vivo using a low dose of oral efavirenz. METHODS: We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre-genotyped for the CYP2B6*6 allele (CYP2B6*1/*1, n = 6; *1/*6, n = 6; *6/*6, n = 5). Subjects were pretreated with clopidogrel (75 mg day(-1) for 4 days), itraconazole (200 mg day(-1) for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0-120 h) and urine (0-24 h) concentrations of efavirenz and its metabolites (7- and 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz) were determined by LC/MS/MS. RESULTS: This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), C(max) and Ae(0,24 h) for 8,14-dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14-dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight-adjusted CL/F of efavirenz (r(2) ≈ 0.4, P < 0.05), differed with CYP2B6*6 genotype and was affected by clopidogrel pretreatment (P < 0.05) but not by itraconazole pretreatment. CONCLUSIONS: The disposition of 8,14-dihydroxy-EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14-dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity in vivo.

Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism.

Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.

LC-MS/MS for the simultaneous analysis of arachidonic acid and 32 related metabolites in human plasma: Basal plasma concentrations and aspirin-induced changes of eicosanoids.

Eicosanoids play an important role in various biological responses and can be used as biomarkers for specific diseases. Therefore, we developed a highly selective, sensitive, and robust liquid chromatography-tandem mass spectrometric method to measure arachidonic acid and its 32 metabolites in human plasma. Sample preparation involved solid phase extraction, which efficiently removed sources of interference present in human plasma. Chromatographic separation was performed using a Luna C(8)-column with 0.5mM ammonium formate buffer and acetonitrile as the mobile phase under gradient conditions. Detection was performed using tandem mass spectrometry equipped with an electrospray ionization interface in negative ion mode. The matrix did not affect the reproducibility and reliability of the assay. All analytes showed good linearity over the investigated concentration range (r>0.997). The validated lower limit of quantitation for the analytes ranged from 10 to 400pg/mL. Intra- and inter-day precision (RDS%) over the concentration ranges for all eicosanoids were within 16.8%, and accuracy ranged between 88.1 and 108.2%. This assay was suitable for the determination of basal plasma levels of eicosanoids and the evaluation of effect of aspirin on eicosanoid plasma levels in healthy subjects.

Effect of CYP2C19 genetic polymorphism on pharmacokinetics and pharmacodynamics of a new proton pump inhibitor, ilaprazole.

It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(τ)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(τ) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants.

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials.

Innovative attempts have been made to overcome nonproductivity and high expenditure in the clinical stages of new drug development. Microdosing studies using subpharmacological doses provide early insight into the body's disposition toward candidate compounds, and are innovative exploratory trials that can promote productivity in drug development. Highly sensitive analytical technology is crucial in microdosing studies that employ qualitative and quantitative assays of target materials in humans. Accelerator mass spectrometry (AMS) has facilitated the adoption of a human microdosing study in the early phase of clinical drug development. Results derived from AMS microdosing studies using labeled compounds can provide various types of information for candidate selection, including pharmacokinetic characteristics and metabolic profiles of candidate compounds. The applicability of microdosing studies is currently expanding into absolute bioavailability and mass balance studies. Although it remains uncertain whether microdosing adequately predicts the pharmacokinetics of therapeutic doses, further development of microdosing studies using AMS may benefit the field of new drug development and could pose a new challenge to researchers. The use of advanced technology in candidate selection will contribute to improved productivity and competitiveness in pharmaceutical research and development. The introduction of microdosing studies using AMS in Korea will present a newly applicable method for innovative clinical trials and contribute to development potential in global competition.

The disposition of three phosphodiesterase type 5 inhibitors, vardenafil, sildenafil, and udenafil, is differently influenced by the CYP3A5 genotype.

OBJECTIVES: This study was conducted to compare the effect of CYP3A5*3 genotype on the disposition of three phosphodiesterase type 5 inhibitors (PDE5Is), vardenafil, sildenafil, and udenafil, because our previous in-vitro microsomal incubation study showed that the relative contribution of CYP3A5 enzyme to their metabolism was different among these PDE5Is. METHODS: An open-label three-way crossover study was performed with a single oral dose of PDE5Is (20 mg vardenafil, 100 mg sildenafil, or 200 mg udenafil) in 21 healthy men carrying CYP3A5*1/*1, *1/*3, or *3/*3. After each dose, plasma concentrations of the parents and their major metabolites were measured up to 24 or 48 h. RESULTS: The AUC(∞) and C(max) of vardenafil were 2.9-fold and 3.1-fold higher in CYP3A5*3/*3 carriers than in individuals with CYP3A5*1/*1 (P=0.003 and 0.002, respectively). The AUC(∞) and C(max) of sildenafil were 1.5-fold and 1.7-fold higher in CYP3A5*3/*3 carriers compared with individuals with CYP3A5*1/*1, but the statistical difference of both parameters among genotype groups was not observed. The disposition of udenafil differed little among groups in relation to the CYP3A5*3 allelic variant. CONCLUSION: These results suggest that the disposition of these PDE5Is are differently influenced by the CYP3A5*3 genotype of individual participants. The CYP3A5*3 genotype affects the oral disposition of vardenafil significantly. The pharmacokinetic diversity of PDE5Is in relation to CYP3A5 genotype may lead to the clinical response variation and remains to be evaluated.

Discovery of a novel allelic variant of CYP2C8, CYP2C8*11, in Asian populations and its clinical effect on the rosiglitazone disposition in vivo.

The objectives of this study were to identify the genetic variants of CYP2C8, analyze CYP2C8 single nucleotide polymorphisms (SNPs), and characterize their functional consequences in the CYP2C8 substrate drug rosiglitazone in humans. The direct full sequencing of CYP2C8 genomic DNA was performed in a Korean population (n = 50). A total of 17 CYP2C8 variants including a novel coding variant (E274Stop) were identified. The novel CYP2C8 E274Stop variant was assigned as CYP2C8*11 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Seventeen SNPs were used to characterize linkage disequilibrium, haplotype structures, and haplotype tagging SNPs. Genotyping for CYP2C8*11 in an extended set of Koreans (n = 400), whites (n = 100), Han Chinese (n = 348), Vietnamese (n = 100), and African Americans (n = 93) was performed by a newly developed pyrosequencing method. The frequency of CYP2C8*11 was 0.3% in Koreans, 1% in Vietnamese, and 0.14% in Chinese. However, none of the whites or African Americans contained the CYP2C8*11 allele. Subjects with CYP2C8*1/*11 exhibited higher plasma concentration-time profiles of rosiglitazone than those of nine control subjects carrying CYP2C8*1/*1. The area under the concentration-time curve and peak plasma concentration of rosiglitazone in individuals carrying CYP2C8*1/*11 (n = 5) were 54 and 34% higher than the mean values observed in the control subjects carrying CYP2C8*1/*1 (P = 0.015 and P = 0.025, respectively). In summary, this is the first report to characterize the allele frequency and haplotype distribution of CYP2C8 in a Korean population, and it provides functional analysis of a new variant CYP2C8*11. Our findings suggest that individuals carrying CYP2C8*11, a null allele found in Asians only, may have lower activity for metabolizing CYP2C8 substrate drugs.

Robust CYP2D6 genotype assay including copy number variation using multiplex single-base extension for Asian populations.

BACKGROUND: We developed a CYP2D6 genotyping method that includes copy number variation (CNV) and recently known functional haplotypes using multiplex single-base extension (SBE). METHODS: Twelve CYP2D6 alleles (*1, *2, *5, *10, *14, *18, *21, *41, *49, *52, *60, and a duplication of CYP2D6) were genotyped using 2 PCR reactions followed by multiplex SBE with 10 primers and singleplex SBE with 1 primer. The result from 758 Korean samples was validated by comparison with the results of direct sequencing or other genotyping methods. We also genotyped 89 Chinese and 122 Vietnamese subjects to determine the presence of recently identified functional alleles. RESULTS: All 12 CYP2D6 alleles, including gene deletion and duplication, were obviously discriminated. The concordance rate was 100% between our method and other methods. Our method also covered over 98% of the CYP2D6 genotypes in Japanese and Chinese subjects based on reported data. In addition to published genotypes, *14, *21, *41, *49, and *52 were found in about 5% in Chinese and Vietnamese. CONCLUSIONS: The CYP2D6 genotyping method may be clinically applicable for Asian populations. The method can be improved easily to cover other ethnic groups by utilizing additional haplotype tagging SNPs.

Effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Woohwangcheongsimwon suspension has traditionally been used for the treatment and prevention of stroke, hypertension, palpitations, convulsions and unconsciousness in various Asian countries. Woohwangcheongsimwon suspensions showed an inhibitory effect on CYP2B6 activity in vitro. Two terpenoids, borneol and isoborneol, are major constituents of woohwangcheongsimwon suspension, and show a competitive inhibition of CYP2B6 with K(i) values of 9.5 and 5.9 microM, respectively. Bupropion undergoes metabolic transformation to the active metabolite, 4-hydroxybupropion, primarily via CYP2B6 both in vivo and in vitro. It is often used as a CYP2B6 substrate for clinical drug-drug interaction studies. Drug interactions may occur between woohwangcheongsimwon suspension and bupropion. WHAT THIS STUDY ADDS: Co-administration with woohwangcheongsimwon suspension did not alter the pharmacokinetics of bupropion or its metabolite, 4-hydroxybupropion. Dosage adjustment of bupropion is unnecessary in patients concomitantly administered the highest recommended daily dose of woohwangcheongsimwon suspension. AIMS: To examine the effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, formed via CYP2B6 in vivo. METHODS: A two-way crossover clinical trial with a 2 week washout period was conducted in 14 healthy volunteers. In phases I and II, subjects received 150 mg bupropion with or without woohwangcheongsimwon suspension four times (at -0.17, 3.5, 23.5 and 47.5 h, with the time of bupropion administration taken as 0 h) in a randomized balanced crossover order. Bupropion and 4-hydroxybupropion plasma concentrations were measured for up to 72 h by LC-MS/MS. Urine was collected up to 24 h to calculate the renal clearance. In addition, the CYP2B6*6 genotype was also analyzed. RESULTS: The geometric mean ratios and 90% confidence interval of bupropion with woohwangcheongsimwon suspension relative to bupropion alone were 0.976 (0.917, 1.04) for AUC(0,infinity) and 0.948 (0.830,1.08) for C(max), respectively. The corresponding values for 4-hydroxybupropion were 0.856 (0.802, 0.912) and 0.845 (0.782, 0.914), respectively. The t(max) values of bupropion and 4-hydroxybupropion were not significantly different between the two groups (P > 0.05). The pharmacokinetic parameters of bupropion and 4-hydroxybupropion were unaffected by woohwangcheongsimwon suspension. CONCLUSIONS: These results indicate that woohwangcheongsimwon suspension has a negligible effect on the disposition of a single dose of bupropion in vivo. As a result, temporary co-administration with woohwangcheongsimwon suspension does not seem to require a dosage adjustment of bupropion.

Itraconazole and rifampin alter significantly the disposition and antihistamine effect of ebastine and its metabolites in healthy participants.

The present study was performed to elucidate the effects of itraconazole and rifampin on the pharmacokinetics and pharmacodynamics of ebastine, a nonsedative H1 receptor antagonist. In a 3-way crossover sequential design with 2-week washouts, 10 healthy participants were pretreated with itraconazole for 6 days, rifampin for 10 days, or neither. After oral administration of 20 mg ebastine, blood and urine samples were collected for 72 and 24 hours, respectively, and histamine-induced wheal and flare reactions were measured to assess the antihistamine response for 12 hours. Itraconazole pretreatment decreased the oral clearance of ebastine to 10% (P < .001) and increased the AUC(infinity) of the active metabolite, carebastine, by 3-fold (P < .001). On the other hand, rifampin pretreatment decreased the AUC(infinity) of carebastine to 15% (P < .001), with an enormous reduction in the oral bioavailability of ebastine and significantly reduced histamine-induced skin reactions. From these results, the disposition of ebastine and carebastine seems to be significantly altered by coadministration of itraconazole or rifampin. The antihistamine response after ebastine dosing would be decreased following rifampin pretreatments.

Serum levels of IL-18 and sIL-2R in patients with alopecia areata receiving combined therapy with oral cyclosporine and steroids.

This study was to determine which immunologic factors contribute to the prognosis of patients with alopecia areata (AA) who were receiving oral cyclosporine A and methylprednisolone. Patients with > 25% hair regrowth were defined as responders, and patients exhibiting < or = 25% regrowth were poor-responders. The serum levels of IL-18 and soluble IL-2 receptor (sIL-2R) were measured at baseline in 21 patients with AA and 22 control subjects. The mean serum level of IL-18 in the patients with extensive AA was significantly higher than that in the control subjects. The mean serum concentration of sIL-2R in the AA patients significantly decreased after 1 month of treatment. The mean basal serum level of IL-18 was highest in the responder, whereas the baseline level of sIL-2R was significantly higher in the poor-responder group than other groups. In conclusion, increased serum sIL-2R level and lower IL-18 level at baseline was associated with a poor prognosis in patients with AA.