Among 4 known cytochrome P450 (CYP) 2C genes, CYP2C9 is the most abundantly expressed in the human liver and intestine. CYP2C9 involves in the metabolism of wide variety of clinically used drugs including anticoagulant warfarin, antidiabetic tolbutamide, anticonvulsant phenytoin, hypertensive agent losartan, and several nonsteroidal anti-inflammatory drugs. More than 36 single nucleotide polymorphisms (SNPs) have been identified in human CYP2C9 at present. Two known allelic variants CYP2C9*2 and CYP2C9*3 have been reported to be associated with development of clinically significant adverse reactions, such as life-threatening bleeding episodes with warfarin use and the severe toxicity with phenytoin. Further clinical studies are required for the recently found defective CYP2C9 SNPs, such as CYP2C9*4, *5, *6, *9, *11, *13, *15 and *25. The present report reviews the current progress in the identification and functional studies of CYP2C9 SNPs and the clinical relevance of CYP2C9 genotype on the personalized pharmacotherapy.

Clinical trials are more common worldwide, but there are some concerns on the protection of the public and disclosure of all information about investigational products including pharmaceuticals, biologic agents and even medical devices. In order to disclose all kinds of information about clinical trials, clinical trial registration was developed according to the decision by United States Food and Drug Administration (US FDA) and World Health Organization (WHO) separately. From July 1st in 2005, phase II to IV trials which are 'clinically directive' should be registered in the registries that are 1) easily accessible to the public, 2) free of charge, 3) open to all registrants and not for profits, 4) electronically searchable and 5) capable of ensuring validity of the registration data. This kind of registries are strongly supported by International Committee of Medical Journal Editors (ICMJE). The committee announced that they will consider a trial for publication only if it has been registered before the enrollment of the first patient. So, many multinational pharmaceutical companies have already implemented the registration and even investigators are requested to register the investigator sponsored trials in the clinical trials registry such as ClinicalTrials.gov. In this article, I will explain history, requirement and actual method of registration in clinical trials registry for better understanding and implementation of clinical trials in Korea.

A quality is a set of characteristics that a product and service have to satisfy requirements of the customers; research subjects, sponsors, regulatory authorities worldwide, hospitals and IRB/IECs. In Clinical Research products are information from the clinical research process and requirements are law & regulations, GCP, ethical standards, trial protocol, budget and timeline. Quality Control(QC) of Clinical Research is activity that checks on the compliance of the trial process & reliability and credibility of data. QC is performed at every step of the clinical trial process and applied to each stage of data handling. Quality Assurance (QA) of Clinical Research is independent audits of all trial-related processes & functions. QA is performed by QA team not involved in the research process and assess efficiency of sponsors' QC processes. Quality Management System(QMS) is a set of tools to ensure, control, maintain, and improve quality. QMS supports continuous Quality Improvement(QI). QI is peformed by FOCUS-PDLA cycle.

This randomized, single-blind, two-sequence, two-period crossover study in 24 healthy volunteers with a 2-week washout interval compared pharmacokinetics of two salt forms of amlodipine formulations, the newly developed formulation (amlodipine orotate, $Orodipine^{(R)}$, Dong-A Pharmaceutical Company, Limited, Korea) to increase the dissolution rate at higher gastric pH conditions and the original formulation (amlodipine besylate, $Norvasc^{(R)}$, Pfizer Incorporated, Korea). Methods: Plasma samples were obtained over 144 h after a single oral dose of 10 mg amlodipine, two tablets for each formulation. Plasma amlodipine concentrations were analyzed by combined liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization (ESI) using multiple reaction monitoring (MRM). From the amlodipine plasma concentration versus time curves, the amlodipine pharmacokinetic parameters were determined by non-compartmental method. Results: Mean of area under the plasma amlodipine concentration-time curve from time 0 to time infinity $(AUC_{0-{\infty}})$ of Orodipine was $336ng{\cdot}h/mL$ (coefficient of variation (CV)=31.3%) and that of $Norvasc^{(R)}$ was $329ng{\cdot}h/mL$ (CV=38.3%). Mean of maximum observed plasma amlodipine concentration $(C_{max})$ of Orodipine was 6.89 ng/mL (CV=25.8%) and that of $Norvasc^{(R)}$ was 6.46 ng/mL (CV=32.0%). The percent ratios of 90% confidence intervals of $Orodipine^{(R)}/Norvasc^{(R)}$ were $99{\sim}124%\;for\;(C_{max})\;and\;94{\sim}118%\;for\;AUC_{0-{\infty}}$ and the means of terminal elimination half-life $(t_1/2{\beta})$ of amlodipine were 44.0 h (CV=17.5%) for $Orodipine^{(R)}$ and 42.6 h (CV=16.7%) for $Norvasc^{(R)}$ respectively. Conclusion: Since amlodipine orotate and amlodipine besylate showed similar pharmacokinetic characteristics, alteration of the salt form did not affect the pharmacokinetics of amlodipine.

연구배경: $HPP^+$와 reduced haloperidol(RHAL) 및 haloperidol의 분포 및 소실(disposition)에 대한 P-glycoprotein(P-gp)의 관련성을 평가하였다. 방법: P-gp-(-)-MDA435/LCC6 세포주와 P-gp-과발현-$MDA435/LCC6^{MDR1}$ 세포주에서, $HPP^+$와 RHAL 및 haloperidol의 세포내 축적을 비교하였고 잘 알려진 P-gp 기질인 doxorubicin의 세포내 축적에 대한 다약제내성 환원 효과(MDR1-reversing effect)를 평가하였다. 결과: Haloperidol과 RHAL은 두 세포주에 용량 의존적으로 축적되었고 경미한 다약제내성 환원 효과를 보였으나, $HPP^+$는 매우 적게 축적되었으며 다약제내성 환원효과가 없었다. Haloperidol과 RHAL 및 HPP+의 축적 정도는 두 세포주 간에 차이가 없었다. 결론: P-gp가 $HPP^+$와 RHAL 및 haloperidol의 분포 및 소실에 영향을 주지 않으므로, 이 화합물들이 뇌로 분포하는 것에 P-gp의 기질들과 유의하게 상호작용하지는 않을 것이다.

Zonisamide has been used for various types of epilepsy, especially for refractory epilepsy. Method: An open-label, one-period, single-dose study was performed in 10 healthy Korean male volunteers with the approval of an institutional review board to determine the pharmacokinetics of zonisamide after a single 100 mg oral dose of zonisamide. Serial blood samples were obtained at fixed time points, over 216 h (baseline (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 72, 120, 168, and 216 h after administration). Zonisamide concentrations in plasma were measured by reversed-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detector set at an wavelength of 280 nn. The results of the plasma analyses were subjected to non-compartmental pharmacokinetic analysis. Results: The maximum observed plasma zonisamide concentration $(C_{max})\;was\;1.3{\pm}0.3\;(mean{\pm}standard\;deviation){\mu}g/mL\;at\;4.0{\pm}1.6hr$ of time to reach maximum observed plasma concentration $(T_{max})$. The value of area under the plasma zonisamide concentration versus time curve from the dosing to the last quantifiable concentration $(AUC_{0-last}=87.7{\pm}15.6{\mu}g{\cdot}h/mL)$ was about 82% of AUC from the dosing to time infinity $(AUC_{0-{\infty}}=106.8{\pm}22.3{\mu}g{\cdot}h/mL)$. The calculated mean residence time (MRT) of zonisamide in the body was $128.6{\pm}23.7h$, and the means of apparent oral total body clearance (CL/F) and volume of distribution $(V_dF)4 were $0.97{\pm}0.21L/h\;and\;1.9{\pm}0.3L/kg$, respectively. Conclusion: The present pharmacokinetic data of zonisamide would be useful for designing clinical trials including the bioequivalence test in Koreans.

Godex is a mixture of hepadif and biphenyl dimethyl dicarboxylate (DDB), which has hepatoprotective activity. This study evaluated the effect of Godex on biochemical items associated with liver function and hepatitis B virus DNA level to patients with chronic hepatitis, fatty liver and liver cirrhosis. A total of 242 patients with chronic hepatitis, fatty liver and liver cirrhosis who visited to 12 medical centers from Sep. 2002 to Feb. 2005 and have no other medicines except it were enrolled in this study. We retrospectively evaluated the changes of biochemical items such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, albumin, prothrombin time, platelet count and hepatitis B virus DNA level before and at 1, 3, 6, 9 and 12 months after the Codex treatment. In patients with chronic hepatitis, ALT and total bilirubin have shown statistically significant changes (p<0.05). In patients with fatty liver and liver cirrhosis, the ALT level alone was significantly changed (p<0.05). Otherwise, hepatitis B virus DNA level was not changed Even if some biochemical items were improved in patients with chronic hepatitis, fatty liver and liver cirrhosis after Godex treatment it did not affect the change of hepatitis B virus DNA level.