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A simple, rapid and sensitive LC–MS/MS method in positive ion mode was developed and validated to determine CKD-501, lobeglitazone, in human plasma and urine using glipizide as an internal standard (IS). Lobeglitazone is a novel thiazolidinedione (TZDs)-based peroxisome proliferator-activated receptor (PPAR) agonist, used for the management of type-2 diabetes. After mixing the IS, dissolved in acetonitrile, with a plasma or urine sample containing lobeglitazone, 10 μL of supernatant was injected into the LC–MS/MS system. Quantification was performed in the multiple reaction monitoring (MRM) mode using transition of 481.5 → 152.2 (m/z) for lobeglitazone and 446.1 → 321.2 (m/z) for the IS. The method showed good linearity over concentration ranges of 0.5–1,000 ng mL−1 for plasma and 0.2–250 ng mL−1 for urine (r 2 ≥ 0.9996). The mean percent extraction recovery of lobeglitazone was 90.8 % for plasma and 87.3 % for urine, while the recoveries of the IS were greater than 86.4 % for both. The intra-day and inter-day precision of plasma ranged from 1.1 to 3.7 and 2.5 to 3.3 % (RSD), respectively, and the intra- and inter-day precision of urine ranged from 1.5 to 2.7 and 3.2 to 3.5 %, respectively. This method is simple, sensitive, and applicable for the pharmacokinetic study of lobeglitazone in human plasma. Most of the urine concentrations of lobeglitazone were below the LLOQ because the lobeglitazone is extensively metabolized.

Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate. To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration–occupancy relationship in terms of EC50 between patients and healthy volunteers. Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [11C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D2 receptor occupancy using E max model and calculated EC50. The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC50 was 7.6 ng/ml (95% confidence interval (CI) 6.2–9.0) in healthy volunteers and 8.6 (95% CI 7.4–9.9) in patients. The antipsychotic concentration–occupancy relationship in patients can be estimated from the EC50 data of healthy volunteers.

A simultaneous simple, rapid, and sensitive LC–MS–MS method was developed and validated for the determination of HM30181A, [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl]-4,5-dimethoxy-phenyl]amide, as a P-glycoprotein inhibitor and its two metabolites, M1 and M2, in human plasma using docetaxel as an internal standard (IS). The analytes were extracted from 200 μL of biological sample by liquid–liquid extraction using 1 mL of methyl-t-butyl ether. Chromatographic separation was carried on a Luna C8 column at 30 °C with mobile phase consisting of distilled water with 0.1% formic acid and acetonitrile (75:25, v/v) at a flow rate of 0.7 mL min−1 for human plasma samples. The method was linear over concentration ranges of 0.5–50, 0.1–10, and 0.1–10 ng mL−1 for HM30181A, M1, and M2, respectively, in human plasma. The values of coefficient variation for the assay precision were

YKP1358 is a novel serotonin (5-HT2A) and dopamine (D2) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D2 receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D2 receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [11C]raclopride. The D2 receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D2 receptor occupancy by YKP1358 increased to 53–83% at 2 h, and then decreased afterwards, ranging from 40–64% at 5 h to 20–51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D2 receptor occupancy that was well predicted by a sigmoid Emax model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D2 receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D2 receptor occupancy. Clinical Pharmacology & Therapeutics (2007) 81, 252–258. doi:10.1038/sj.clpt.6100049

Background Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1B1 (OATP1B1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. Methods Twenty–four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1–8 mg) were further investigated. Subjects were grouped according to OATP1B1 genotype. Dose–normalized area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. Results Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8 ± 13.3, 54.4 ± 12.4, and 68.1 ± 16.3 ng · h · mL−1 · mg−1 (mean ± SD), respectively, with significant differences between all 3 groups (P = .008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin Cmax values were 13.2 ± 3.3, 18.2 ± 5.7, and 29.4 ± 9.6 ng · mL−1 · mg−1 in groups 1, 2, and 3, respectively, and also showed significant differences (P = .003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or Cmax values of pitavastatin lactone. Conclusion OATP1B1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP1B1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone. Clinical Pharmacology & Therapeutics (2005) 78, 342–350; doi: 10.1016/j.clpt.2005.07.003

Objective Our objective was to investigate the effect of the uridine 5′-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism on the pharmacokinetics and pharmacodynamics of lorazepam in basal, inhibited, and induced metabolic states in healthy normal volunteers. Methods Twenty-four healthy subjects were enrolled and grouped into UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic and pharmacodynamic profiles of intravenous lorazepam were characterized before and after inhibition with 600 mg valproate once daily for 4 days and after induction with rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 10 days between. The plasma concentrations of lorazepam and lorazepam glucuronide were analyzed before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours after lorazepam administration by liquid chromatography-tandem mass spectrometry. Visual analog scale assessments and psychomotor coordination tests were administered before and up to 12 hours after drug administration. Results The UGT2B15*2/*2 group showed 0.58-fold (95% confidence interval, 0.43–0.72; P

Background and Objectives There have been considerable disagreements regarding the influence of MDR1 (ABCB1) polymorphisms on the disposition of P-glycoprotein (P-gp) substrates. We speculated that the unknown function of the A allele of exon 21 G2677T/A (Ala893Ser/Thr) provides one of the reasons for the contradictory results. This study was performed to clarify the effects of major MDR1 gene polymorphisms, including a variant A allele in exon 21, on fexofenadine pharmacokinetics. Methods We investigated the occurrence of 3 high-frequency single-nucleotide polymorphisms (SNPs) in exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) of the MDR1 gene in 232 healthy Koreans, using a polymerase chain reaction-restriction fragment length polymorphism method, and performed haplotype analysis on these 3 SNPs. A single oral dose of 180 mg fexofenadine hydrochloride was administered to 33 healthy Korean male volunteers, who were divided into 6 groups based on the MDR1 genotype for the G2677T/A polymorphism in exon 21 and the C3435T polymorphism in exon 26. Results A strong linkage disequilibrium was observed among the 3 SNPs. The frequencies of the 4 major haplotypes, 1236C-2677A-3435C, C-G-C, T-G-C, and T-T-T, were 16.4%, 18.6%, 21.6%, and 32.2%, respectively. Fexofenadine disposition varied considerably among the groups. In the 2677AA/3435CC genotype group (n = 3), the values of area under the concentration-time curve from time 0 to 24 hours [AUC(0–24)] were significantly lower (P = .014) than those of the other 5 genotype groups (GG/CC, GT/CT, TT/TT, GA/CC, and TA/CT). As compared with the 2677GG/3435CC subjects, the AUC(0–24) values were 17% lower in the 2677AA/3435CC subjects and 47% higher in the 2677TT/3435TT subjects (GG/CC versus AA/CC versus TT/TT, 4017 ± 1137 ng · h/mL versus 3315 ± 958 ng · h/mL versus 5934 ± 2,064 ng · h/mL; P = .018). By stratification for genotypes at position 3435, homozygous 3435TT subjects were found to have significantly higher AUC(0–24) (P = .024) and maximum plasma concentration (P = .040) values than CC subjects [AUC(0–24), 5934 ± 2064 ng · h/mL versus 3998 ± 1241 ng · h/mL; maximum plasma concentration, 958 ± 408 ng/mL versus 673 ± 242 ng/mL]. Conclusions The plasma concentrations of fexofenadine after a single oral administration were lower in 2677AA/3435CC subjects than in subjects with the other 5 genotype combinations of the SNPs of G2677T/A and C3435T. These findings confirm the importance of analyzing MDR1 haplotypes and provide a plausible explanation for the conflicting results regarding the effect of MDR1 polymorphisms on the disposition of P-gp substrates. Clinical Pharmacology & Therapeutics (2004) 76, 418–427; doi: 10.1016/j.clpt.2004.08.002

Objective Our objective was to investigate the effect of the CYP3A5 genotype on the systemic clearance of midazolam in constitutive, inhibited, and induced metabolic conditions. Methods Nineteen healthy volunteers were grouped with regard to the CYP3A5*3 allele, into homozygous wild-type (CYP3A5*1/*1, n = 6), heterozygous (CYP3A5*1/*3, n = 6), and homozygous variant-type (CYP3A5*3/*3, n = 7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days) and also after rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. Results The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the CYP3A5*3/*3 group showed a greater decrease in systemic clearance than was seen in the CYP3A5*1/*1 group (8.5 ± 3.8 L · h−1 · 70 kg−1 versus 13.5 ± 2.7 L · h−1 · 70 kg−1, P = .027). The 1′-hydroxymidazolam–to–midazolam area under the plasma concentration–time curve ratio was also significantly lower in the CYP3A5*3/*3 group (0.58 ± 0.35 versus 1.09 ± 0.37 for the homozygous wild-type group, P = .026). Conclusions The CYP3A5 genotype did not affect the pharmacokinetics of intravenous midazolam in the basal or induced states. However, during cytochrome P450 (CYP) 3A inhibition by itraconazole, individuals carrying the CYP3A5*1 allele were found to be less susceptible to changes in systemic clearance and showed higher 1′-hydroxymidazolam–to–midazolam area under the plasma concentration–time curve ratios, probably resulting from the relatively CYP3A4-specific inhibition caused by itraconazole. Clinical Pharmacology & Therapeutics (2004) 76, 104–112; doi: 10.1016/j.clpt.2004.03.009

To evaluate the effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. A single 5-mg capsule of tropisetron was administered orally to 13 healthy subjects. Plasma concentrations were determined by validated HPLC procedures and data were analyzed by using noncompartmental linear PK methods. Four alleles, CYP2D6*1, CYP2D6*2 ×2, CYP2D6*5, and CYP2D6*10, were identified by PCR. Thirteen subjects, consisting of two homozygous carriers of the wild type allele (*1/*1), four heterozygous carriers of poor metabolizer (PM)-associated allele (*1/*10), six homozygous carriers of PM-associated alleles (four with *10/*10 and two with *5/*10), and one carrier of a duplicated allele *1/*2 ×2. All tested pharmacokinetic parameters (AUCinf, AUCinf NL70, Cmax, CmaxNL70, T1/2, and Tec) were significantly different among four different genotypic groups. The mean AUCs of carriers with the heterozygous PM-associated allele and the homozygous PM-associated allele were 1.9- and 6.8-higher than those of carriers with the wild type allele, respectively. In contrast, the mean AUC of carriers with a duplicated allele was 0.5-fold lower than that of those carriers with the wild type allele. The presence of CYP2D6*5, CYP2D6*10, and CYP2D6*2 ×2 has an important impact on the pharmacokinetics of tropisetron, which may influence clinical response to tropisetron therapy.

Objective Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs. Methods Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study. Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups. During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences. Results Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians. This difference decreased to 1.3 when normalized for body weight. Significant correlation between the AUCs of the two drugs was not evident. Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans. Conclusions Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes. Clinical Pharmacology & Therapeutics (2001) 70, 228–236; doi: 10.1067/mcp.2001.117703

Background Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study. Methods The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. Results The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed. Conclusion Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers. Clinical Pharmacology & Therapeutics (2001) 69, 266–273; doi: 10.1067/mcp.2001.114231

Since Good Clinical Practice (GCP) was enacted in Korea in 1995, many noticeable changes occurred in the pharmaceutical industry. GCP prompted pharmaceutical companies to introduce and maintain quality clinical research systems. This paper presents the results of two surveys (in 1995 and 1998) to evaluate how the implementation of GCP has improved clinical trial practice and the working environment in the Korean pharmaceutical industry. Improvements were most evident in local companies, but organizational support was not as consistent as necessary. With the scheduled upgrade of the Korean GCP to the International Conference on Harmonization (ICH) standard in 2000, the authors expect that more global trials will be performed in Korea.

Objective To evaluate the relationship between the metabolic ratio (MR) of metoprolol, CYP2D6*10B genotype, and the disposition of paroxetine in Korean subjects. Methods A single 40–mg dose of paroxetine was administered orally to one poor metabolizer and 15 healthy subjects recruited from 223 Korean extensive metabolizers whose phenotypes were predetermined by use of the metoprolol MR. Genotypes were determined by allele-specific polymerase chain reaction and the GeneChip microarray technique. Pharmacokinetic parameters were estimated from plasma concentrations of paroxetine for more than 240 hours after the oral dose. Results The oral clearance and area under the plasma concentration versus time curve (AUC) of paroxetine were best described by a nonlinear relationship with metoprolol MR at correlation coefficients of 0.82 and 0.91, respectively (P < .05). Nine extensive metabolizer who were either homozygous or heterozygous for CYP2D6*10B had significantly lower oral clearance values of paroxetine than six extensive metabolizers with CYP2D6*1/*1. The AUC of paroxetine in subjects who were homozygous for CYP2D6*10B (666.4 ± 169.4 ng/mL · h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 ± 55.9 ng/mL · h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 ± 816.9 ng/mL · h) than that of subjects who were homozygous CYP2D6*10B/*10B mainly because of two atypical subjects whose metoprolol MR was not associated with the CYP2D6*10B genotype and who showed greater AUC and lower oral clearance than subjects with homozygous CYP2D6*10B. Conclusions The CYP2D6 activity measured by metoprolol MR was a strong predictor of paroxetine disposition in Korean extensive metabolizers. In general, the extensive metabolizers with the CYP2D6*10B allele seemed to have higher plasma concentrations of paroxetine than extensive metabolizers with the wild-type CYP2D6 genotype. However, quantitative prediction of paroxetine disposition from the CYP2D6*10B genotype alone was not perfect because several Korean extensive metabolizers had metoprolol MRs that were not associated with the genotype. Clinical Pharmacology & Therapeutics (2000) 67, 567–576; doi: 10.1067/mcp.2000.106128

Rationale: CNS-active drugs produce specific electroencephalographic changes and the concentration-effect relationship of antipsychotics may be elucidated by adopting electroencephalography (EEG) as an effect measurement tool. Objective: The purpose of the present study was to determine the concentration-effect relationship of risperidone by assessing the EEG effect after oral administrations of single dose risperidone in healthy young males. Methods: Nine healthy male volunteers received a 1 mg single oral dose of risperidone according to a placebo controlled crossover design. Plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone were measured by radioimmunoassay. Quantitative EEG parameters were obtained for each of four frequency bands through spectral EEG analysis. The difference in the absolute power in the delta frequency band for the F3 lead between risperidone and placebo was used as a drug effect parameter. For pharmacokinetic-pharmacodynamic modeling, the hypothetical effect compartment kinetically linked to plasma by a first-order process was postulated. All curve fittings were done with the non-linear curve-fitting program NONLIN. Results: Our results showed that absolute powers in delta and theta frequency bands were higher for risperidone administration than for placebo at all EEG leads, and the maximum effects were detected at about 3 h after administration of the drug. The hysteresis loop was observed in the plot of plasma concentration of risperidone or sum of risperidone and 9-hydroxyrisperidone (Cp) versus EEG effect for each subject. A linear model adequately described the relationship between the effect compartment concentrations (Ce) and EEG effects, and the two limbs of hysteresis in the Cp-effect plot were collapsed in the Ce-effect plot for risperidone or risperidone plus 9-hydroxyrisperidone. Conclusion: The increases of absolute power for delta and theta frequency bands of EEG were induced by single oral administration of risperidone. The linear PK-PD model fit well with the relationship between effect compartment concentrations (Ce) and EEG effects of risperidone.

Following government initiatives in the mid-1980s to change the mechanism by which new drugs are approved, the popularity of clinical drug trials has increased among the drug industry and academia of Korea. The Korean drug authority requested in the early 1990s that the drug industry maintain the minimum principles of the Declaration of Helsinki, such as establishing institutional review board (IRB) reviews and obtaining written informed consent for regulatory controlled drug trials. The Korean Good Clinical Practice (KGCP) guidelines were legislated and became effective as of October 1, 1995. Although implementation of the KGCP increased the burden on the drug industry and on medical institutions, its enforcement has brought about remarkably positive changes in the infrastructure and quality of clinical drug trials in this country. Moreover, it has promoted collaborative educational activities between the government and academic institutions. These improvements will likely raise the standards for other c...

The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.

With increasing concern about the investigational use of drugs developed outside of Korea, the Korean drug regulatory authorities began discussing the concept of good clinical practice in the early...

We studied the genetically determined hydroxylation polymorphism of S-mephenytoin in a Korean population (N = 206) and the pharmacokinetics of diazepam and demethyldiazepam after an oral 8 mg dose of diazepam administered to the nine extensive metabolizers and eight poor metabolizers recruited from the population. The log10 percentage of 4-hydroxymephenytoin excreted in the urine 8 hours after administration showed a bimodal distribution with an antimode of 0.3. The frequency of occurrence of the poor metabolizers was 12.6% in the population. In the panel study of diazepam in relation to the mephenytoin phenotype, there was a significant correlation between the oral clearance of diazepam and log10 urinary excretion of 4-hydroxymephenytoin (rs = 0.777, p less than 0.01). The plasma half-life of diazepam in the poor metabolizers was longer than that in the extensive metabolizers (mean +/- SEM, 91.0 +/- 5.6 and 59.7 +/- 5.4 hours, p less than 0.005), and the poor metabolizers had the lower clearance of diazepam than the extensive metabolizers (9.4 +/- 0.5 and 17.0 +/- 1.4 ml/min, p less than 0.001). In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01). The findings indicate that the Korean subjects have a greater incidence of poor metabolizer phenotype of mephenytoin hydroxylation compared with that reported from white subjects and that the metabolism of diazepam and demethyldiazepam is related to the genetically determined mephenytoin hydroxylation polymorphism in Korean subjects.

We have investigated changes in the pharmacokinetics of prednisolone caused by co-administration or discontinuation of rifampin. Serial IV pharmacokinetic studies of prednisolone (1 mg/kg) in groups of 3 patients over a 1 month period of rifampin co-treatment or after its withdrawal, revealed significant changes in the area under the curve, the total clearance, the non-renal clearance and the half-life. The changes in the pharmacokinetic parameters reached a 1.5 to 2-fold plateau after 2 weeks and the half maximal effect was attained within 5 days. Neither the volume of distribution nor the protein binding of prednisolone were significantly altered.

Dihydrotesterone (DHT) converted by 5-alpha-reductase from testosterone is thought to be the androgen primarily responsible for the development of Benign Prostatic Hyperplasia. Dutasteride is a potent and specific irreversible competitive inhibitor of 5-alpha-reductase type 1 and type 2 for control of BPH. The aim of this study is to evaluate the effect of genetic polymorphism of SRD5A2 on the pharmacodynamics of dutasteride by PK-PD modeling approach. We conducted a phase I clinical study of a single oral 0.5mg dose of dutasteride in 30 healthy Korean male volunteers. We also obtained genotype of SRD5A2 V89L, coding gene of 5-alpha-reductase type 2. Data were analyzed by nonlinear mixed effect modeling using NONMEM. We used a indirect response model to explain the PK-PD characteristics. PK parameters were similar to those of other previous studies (ka = 2.79 h-1, Vd = 530 l, Cl = 10.7 lh-1). Drug concentration corresponding to 50% suppression of enzyme activity(IC50) was about 3 fold smaller in SRD5A2 V89L homomutant group(L/L) than wild type group(V/V) in PK-PD model incorporated genotype as covariate to IC50. (IC50: V/V=0.375 ng/ml, L/L=0.102 ng/ml) These findings suggest dutasteride can be more potently acting in person who have SRD5A2 V89L mutation. It is consistent with the result of in vitro inhibition study. A PK/PD modeling approach was useful to find the effect of genetic polymorphism on the PD of 5-alpha-reductase inhibitor. Clinical Pharmacology & Therapeutics (2004) 75, P12–P12; doi: 10.1016/j.clpt.2003.11.044

The effect of age on theophylline kinetics was examined in six normal young men and six elderly men. There were no age-associated differences in theophylline volume of distribution, total clearance, or t1/2. The unbound fraction of theophylline was significantly raised in the elderly (mean 77.7% vs. 62.3%, p less than 0.001) and was correlated with the serum albumin level (r = -0.7, p less than 0.01). Theophylline nonrenal clearance was not changed, but the total unbound clearance was significantly reduced in the elderly subjects as compared with the young ones (mean 0.744 vs. 1.085 ml/min/kg, p less than 0.05). Creatinine clearance was reduced in the elderly and was significantly correlated with unbound renal clearance (r = 0.6, p less than 0.04). There were no age-related differences in the urinary excretion of theophylline, 1-methyluric acid, 3-methylxanthine, or 1,3-dimethyluric acid. However, significant reduction in unbound renal theophylline clearance (p less than 0.002) as well as the unbound metabolic clearance of 1,3-dimethyluric acid (p less than 0.03), 3-methylxanthine (p less than 0.04), and 1-methyluric acid (p less than 0.02) were observed in the elderly subjects. These observations indicate that both renal and metabolic elimination processes for theophylline are less active in the normal elderly.