Effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in different CYP2D6 genotypes

변지영,이윤정,김영훈,김세형,이충민,배정우,장춘곤,이석용,최창익 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.5

Tamsulosin, a selective antagonist of the a1-adrenoceptor, is primarily metabolized by CYP3A4 andCYP2D6, and tamsulosin exposure is significantlyincreased according to the genetic polymorphism ofCYP2D6. In this study, we investigated the effects of diltiazem,a moderate inhibitor of CYP3A4, on the pharmacokineticsof tamsulosin in subjects with different CYP2D6genotypes. Twenty-three healthy Korean male subjectswith CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, twophaseparallel pharmacokinetic study. On the first day ofstudy (day 1), each subject received a single 0.2 mg oraldose of tamsulosin. After a washout period of 1 week, onday 8, the subjects were given a 60 mg oral dose of diltiazemthree times daily for four days. On day 10, 1 h afterthe morning dose of diltiazem, they received a single0.2 mg oral dose of tamsulosin. The pharmacokineticparameters of tamsulosin in those with and without diltiazemtreatment were compared in subjects with differentCYP2D6 genotypes. After diltiazem treatment, the Cmaxand AUCinf of tamsulosin in each CYP2D6 genotype groupwere significantly increased (p\0.0001 for all). The CL/Fof tamsulosin was also significantly decreased after diltiazemtreatment (both p\0.0001). However, diltiazem didnot affect the t1/2 of tamsulosin in each genotype group. Inconclusion, diltiazem significantly increases exposure totamsulosin regardless of the genotype of CYP2D6. Doseadjustment in the daily maintenance dose of tamsulosinmay improve tolerability and safety in patients receivingdiltiazem.

슬라이딩 모드 제어를 이용한 HDD 하이브리드 제어기 설계 및 안정성 평가

변지영,곽성우,유관호 대한전기학회 2004 전기학회논문지 D Vol.53 No.10-D

This paper presents the design of a new controller for the read/write head of a hard disk drive. The general controller for seeking is the time-optimal control. However if we use only the time optimal control law, this could be vulnerable to chattering effect. To solve this problem, we propose a modified controller design algorithm in this paper. The proposed controller consists of bang-bang control for seeking and sliding-mode control for tracking. Moreover, to test the robustness and stability of control system, a bounded disturbance is selected to maximize a severity index. Simulation results show the superiority of the proposed controller through comparison with time optimal VSC(variable structure control).

CYP2D6 allele frequencies in Korean population, comparisonwith East Asian, Caucasian and African populations,and the comparison of metabolic activity of CYP2D6 genotypes

변지영,김영훈,이충민,김세형,채원기,정의현,최창익,장춘곤,이석용,배정우,이윤정 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.9

Cytochrome P450 (CYP) 2D6 is present in less than about 2% of all CYP enzymes in the liver, but it is involved in the metabolism of about 25% of currently used drugs. CYP2D6 is the most polymorphic among the CYP enzymes. We determined alleles and genotypes of CYP2D6 in 3417 Koreans, compared the frequencies of CYP2D6 alleles with other populations, and observed the differences in pharmacokinetics of metoprolol, a prototype CYP2D6 substrate, depending on CYP2D6 genotype. A total of 3417 unrelated healthy subjects were recruited for the genotyping of CYP2D6 gene. Among them, 42 subjects with different CYP2D6 genotypes were enrolled in the pharmacokinetic study of metoprolol. The functional allele *1 and *2 were present in frequencies of 34.6 and 11.8%, respectively. In decreased functional alleles, *10 was the most frequent with 46.2% and *41 allele was present in 1.4%. The nonfunctional alleles *5 and *14 were present at 4.5 and 0.5% frequency, respectively. The *X 9 N allele was present at a frequency of 1.0%. CYP2D6*1/*1, *1/*2 and *2/*2 genotypes with normal enzyme activity were present in 12.1%, 8.6% and 1.4% of the subjects, respectively. CYP2D6*5/*5, *5/*14, and *14/*14 genotypes classified as poor metabolizer were only present in 4, 2, and 1 subjects, respectively. Mutant genotypes with frequencies of more than 1% were CYP2D6*1/*10 (32.0%), *10/*10 (22.3%), *2/*10 (11.7%), *5/*10 (3.7%), *1/*5 (2.5%), and *10/*41 (1.2%). The relative clearance of metoprolol in CYP2D6*1/*10, *1/*5, *10/*10, *5/*10, and *5/*5 genotypes were 69%, 57%, 24%, 14% and 9% of CYP2D6*wt/*wt genotype, respectively. These results will be very useful in establishing a strategy for precision medicine related to the genetic polymorphism of CYP2D6.

The influences of CYP2C9*1/*3 genotype on the pharmacokineticsof zolpidem

변지영,김영훈,김세형,이충민,정의현,채원기,장춘곤,이석용,이윤정 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.9

Zolpidem is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C9, CYP1A2, CYP2D6 and CYP2C19. The aim of this study was to identify the effects of CYP2C9*3 allele on the pharmacokinetics of zolpidem. Healthy male subjects were divided into two genotype groups, CYP2C9*1/*1 and CYP2C9*1/ *3. They received a single oral dose of 5 mg zolpidem, and the plasma concentrations of zolpidem were determined up to 12 h after drug administration. In addition, since zolpidem is metabolized at a high rate by CYP3A4, the effect of CYP2C9*3 allele on the pharmacokinetics of zolpidem was also observed in the condition where CYP3A4 was suffi-ciently inhibited by the steady-state concentration of clarithromycin, a potent CYP3A4 inhibitor. For this, clarithromycin 500 mg was administered twice daily for 5 days. Plasma concentrations of zolpidem were determined using liquid chromatography-tandem mass spectrometry method. The overall pharmacokinetic parameters of zolpidem were not significantly different between two CYP2C9 genotypes. Even with the potent CYP3A4 inhibitor clarithromycin present at steady-state concentrations, there were no significant differences in the exposure of zolpidem, except for elimination half-life (t1/2). In conclusion, our study suggests that CYP2C9*1/*3 genotype does not affect the plasma exposure of zolpidem.

Effects of genetic polymorphisms of CYP2C19 on the pharmacokinetics of zolpidem

변지영,김영훈,김세형,이충민,정의현,채원기,장춘곤,이석용,이윤정 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.8

Zolpidem is indicated for the short-term treatmentof insomnia and it is predominantly metabolized byCYP3A4, and to a lesser extent by CYP2C19, CYP1A2,and CYP2C9. Therefore, we evaluated the effects ofCYP2C19 genetic polymorphisms on the pharmacokineticsof zolpidem in healthy male subjects. Thirty-two malesubjects were recruited and all subjects were classified intothree groups according to their genotypes: CYP2C19EM(CYP2C19*1/*1, n = 12), CYP2C19IM (CYP2C19*1/*2or *1/*3, n = 10), and CYP2C19PM (CYP2C19*2/*2, *2/*3 or *3/*3, n = 10). The pharmacokinetic parameters ofzolpidem were compared in three CYP2C19 genotypegroups after zolpidem administration with or without aCYP3A4 inhibitor at steady-state concentration. Plasmaconcentrations of zolpidem were determined up to 12 hafter drug administration by liquid chromatography-tandemmass spectrometry method. The maximum plasma concentration(Cmax) differed, but mean total area under theplasma concentration–time curve (AUCinf), half-life (t1/2),and apparent oral clearance (CL/F) of zolpidem administeredalone did not significantly differ among the threedifferent CYP2C19 genotype groups. Furthermore, whenzolpidem was administered with a CYP3A4 inhibitor atsteady-state concentration, there were no significant differencesin any of the pharmacokinetic parameters ofzolpidem in relation to CYP2C19 genotypes. In conclusion,we did not find any evidence for the impact of CYP2C19genetic polymorphisms on the pharmacokinetic parametersof zolpidem.

Inhibition of salivary secretion by tolterodine transdermal patch

변지영,김영훈,김세형,이충민,최창익,배정우,장춘곤,이석용,이윤정 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.12

Tolterodine, a nonselective muscarinic antagonistavailable only as immediate release (IR) or extendedrelease (ER) oral formulations, is used for the treatment ofoveractive bladder (OAB). This study aimed to comparethe efficacy and extent of dry mouth adverse effects oftolterodine transdermal patch to the oral formulation. Thetwo formulations have been examined through the muscarinicreceptor binding tests conducted in bladder andsalivary gland tissues and the salivary secretion tests conductedin rats. Comparable average tolterodine bloodconcentration levels were obtained 3 h after oral administrationof tolterodine 25 mg/kg and 12 h after transdermalapplication of tolterodine patch 6 mg/8 cm2. While Kd inthe bladder tissue increased to a similar degree in bothformulations of tolterodine, Kd in the salivary glandincreased to a greater degree in the oral formulation. Theseresults indicate that similar degree of inhibitory effectswere observed in the bladder for both formulations whileless inhibitory effects were observed in the salivary glandwith tolterodine transdermal formulation compared to theoral formulation. For assessment of salivary secretion,tolterodine transdermal patch 6 mg/8 cm2 applicationresulted in significantly less inhibitory effects than oraltolterodine 25 mg/kg. Therefore, this study suggests thattolterodine transdermal patch could be a useful formulationthat provides uniform and consistent inhibitory effects toeffectively control OAB symptoms with reduced severityof dry mouth in comparison to the oral formulation.

HF-HCl 혼합 용액에서 $EAGLE^{2000TM}$ LCD 유리의 식각에 관한 연구

변지영,Byun, Ji-Young 한국마이크로전자및패키징학회 2008 마이크로전자 및 패키징학회지 Vol.15 No.3

본 연구는 2.5MHF-xMHCl$(x:0\sim8)$ 혼합 용액에서 $EAGLE^{2000TM}$ LCD 유리의 식각에 관한 것이다. 유리의 용해공정에서 율속단계는 HF를 함유한 식각액과 유리와의 반응이었다. 그 증거로는 유리의 두께는 시간에 따라 직선적으로 감소하였고, 식각속도는 교반정도에 무관하게 일정하였으며, 활성화 에너지가 $35\sim45$ kJ/mol 범위였다는 점이다. 순수한 HF만 사용했을 때 보다 HCl이 첨가되면 식각속도는 증가하였고. 그 속도는 HCl 첨가량에 비례하여 증가하였다. 또한 HCl 첨가시 식각 후의 표면은 식각 전과 유사하였다. 이는 HCl 첨가에 의해 $H_{3}O^{+}$ 이온의 농도가 증가하여 각종 불화물의 용해도를 증가시키고, $H_{3]O^{+]$ 이온의 흡착은 Si-O 결합의 결합력을 감소시키기 때문에 일어난 현상으로 사료된다. Etching kinetics of $EAGLE^{2000TM}$ LCD glass was investigated using 2.5MHF-xMHCl$(x:0\sim8)$ acid mixtures. It was concluded that the reaction of HF-containing solutions with the glass was the rate-determining step for the dissolution process when considering following observations; the value of the activation energy $35\sim45$ kJ/mol and insensitivity of the dissolution rate to the etching time and the moving velocity of the glass into the solution. The etching rate linearly increased with increasing the HCl concentration in the etchant. It was also observed that the etched surface was as smooth as the original surface by addition of HCl and increase in etching temperature. This is due to the catalytic role of the $H_{3}O^{+]$ ions in the dissolution process.

엔터테인먼트분야의 새로운 법적 과제 -게임물, 퍼블리시티권 그리고 표현의 자유-미국의 판례가 주는 교훈들

변지영 한국스포츠엔터테인먼트법학회 2009 스포츠와 법 Vol.12 No.2

Game industry is one of the fastest growing industry with its huge population of users. However, the study with respect to legal issues in this area to date is clearly insufficient in Korea. Thus, it is imminent that we examine regulative issues that could arise in the game industry, as a current task at hand in Entertainment law. To complete this mission, it is necessary that we study U.S. common law and statutes, and the purpose and reasons behind such relating to the game industry. In this article, we will first explore Freedom of Speech under First Amendment and publicity rights. Then, the article will review U.S. cases with respect to such rights that involve games. Based upon such study, I would like to find the lesson that U.S. law teaches us in shaping the law and solving legal issues in relation to the game industry. 게임 산업은 디지털 문화 콘텐츠 중 최고의 규모와 사용자를 자랑하는 산업이다. 그 산업의 성장 속도나 시장 규모를 보더라도 게임물은 문화산업 중 큰 축을 이루고 있는 엔터테인먼트 분야이지만, 이 분야에 대한 규범적 연구는 거의 이루어지지 않은 상태이다. 그러므로 우리는 새로운 엔터테인먼트 법적 과제로서 게임물에서 발생할 수 있는 규범적인 문제들을 고찰해보아 향후 바람직한 법적 틀을 고안하는 것이 시급하다고 하겠다. 이를 위해서는 우리보다 이를 위해서는 우리보다 먼저 게임물에 적용될 수 있는 보통법(common law)과 법 규정(statutes)을 만들어 낸 미국의 입법례와 그 법의 의미, 관련법을 만든 과정 등을 반드시 살펴보는 것이 불가피하다 할 것이다. 이 글에서는 게임과 관련된 주요 법적 개념인 미국 수정헌법 제1조 상의 표현의 자유와 미국에서 발생된 퍼블리시티권에 대하여 알아본 다음, 현재 미국에서 문제가 되고 있는 표현의 자유와 퍼블리시티권 관련 주요 판례들을 차례로 살펴볼 것이다. 그리고 이를 바탕으로 우리 법에 있어서도 좀 더 균형적이고 공익적인 해결의 틀을 제시해 보고자 한다.

HF-HCl 혼합 용액에서 유리의 식각에 관한 반응 속도식 결정 (초)

변지영,황주연,소미선 대한금속재료학회 ( 구 대한금속학회 ) 2007 대한금속재료학회 학술대회 개요집 Vol.2007 No.1

눈앞에 다가온 대선, 어떤 세상을 꿈꾸고 있는가?

변지영 우리신학연구소 2017 가톨릭 평론 Vol.8 No.-