니코틴 대사와 CYP2A6 유전자 빈도에 관한 민족적 다형성

권준택 순천향의학연구소 2000 Journal of Soonchunhyang Medical Science Vol.6 No.2

사람의 CYP2A6 유전자는 CYP2A6*1A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 및 CYP2A6*5 대립 유전자가 밝혀져 있으며, nicotine-C 산화반응을 촉매하고 있다. 앞선 보고에 의하면, 일본인에서 nicotine 대사의 개인간 차이는 CYP2A6 유전자 다형성 (genetic polymorphism)과 관련이 있음이 증명된 바 있다. 저자는 Nicotine대사와 CYP2A6 대립 유전자들의 빈도에서 인종간의 차이를 증명하기 위해 209예의 한국인에서 nicotine대사와 CYP2A6의 유전자형을 연구하였다. Nicotine 껌을 투여 후 2시간에 혈장 cotinine/nicotine 비를 계산하여 nicotine대사의 지표로 사용하였으며, CYP2A6의 유전자형은 PCR-RFLP방법으로 결정하였다. 실험 결과 CYP2A6*1A, CYP2A6*1B, CYP2A6*4 및 CYP2A6*5 대립 유전자의 빈도는 한국인 (각각 45.7%, 42.8%, 11.0% 및 0.5%)과 일본인간에는 인종간의 차이를 보였다. 그러나 CYP2A6*2와 CYP2A6*3 대립 유전자형에는 어떠한 차이도 관찰할 수 없었다. 4명의 CYP2A6*4 homozygotes에서는 cotinine형성이 완전히 결여되었으며 그 결과는 일본인에서 관찰된 자료와 일치하였다. CYP2A6*4 heterozygotes에서는 이것이 없는 사람들에 비해 낮은 대사율을 보이는 경향이 있었으며, CYP2A6*1B 대립유전자를 지닌 사람들은 cotinine 형성 능력이 훨씬 높은 경향을 나타내었다. 니코틴 대사의 개인별 차이는 CYP2A6의 유전자 다형과 밀접한 관련이 있음을 확인하였다. 한국인에서 대사율의 probit plot 결과는 0.6의 antimode치를 보여 일본인에서 얻은 결과와 동일하였다. CYP2A6*1B/CYP2A6*4를 가진 한 명의 한국인에서 새로운 CYP2A6 돌연변이가 있는 것으로 보였다. 한국인의 probit plot 결과는 일본인보다 높은 비를 보였으며, 각 유전자형 군에서 한국인 군은 일본인 군에 비하여 유의하게 높은 대사율을 보였다. Cotinine 형성에서 인종간의 차이는 유전학적 소인 외에도 환경인자 및 식이 등의 인자들이 관여할 것으로 보인다.

한국인에서의 CYP2C19m₁과 CYP2C19m₂돌연변이 유전자형의 다형성

권준택,김형기 순천향의학연구소 1998 Journal of Soonchunhyang Medical Science Vol.4 No.1

The S-mephenytoin 4 -hydroxylase (CYP2C19) metabolizes a number of clinically used drugs and shows a marked interethnic difference in the incidence of the poor metabolizer (PM). In the present study, we genotyped 215 healthy unrelated Koreans (64 females, aged 20-41 yr, residing in Chungcheong province) for functionally defective alleles, CYP2C19m1 and CYP2C19m2 Detection of the normal (CYP2C19wt) and defective alleles was performed by polymerase chain reaction/restriction enzyme analysis. The genomic DNA was isolated from peripheral blood. The allelic frequencies of the wild-type (CYP2C19wt) and CYP2C19m1 were 72.6% and 27.4%, and the wild-type (CYP2C19wt) and CYP2C19m2 were 85.1% and 14.9%, respectively. For each CYP2C19m1 and CYP2C19m2 the observed numbers of three genotypes were similar to those calculated in accordance with the Hardy-Weinberg equation. The frequencies of homozygotes for CYP2C19m1, CyP2C19m2 and compound heterozygotes were 9.7%, 2.8% and 4.2%, respectively. The mutants of CYP2C19 were identified in 36 subjects (16.7%). These results suggest that frequency of mutants of CYP2C19 in Koreans resembled the Orientals rather than Caucasians.

한국인에서의 CYP2C19 유전자형의 다형성

권준택,김형기,손동렬,염윤기 순천향의학연구소 2004 Journal of Soonchunhyang Medical Science Vol.10 No.1

The S-mephenytoin 4'-hydroxylase (CYP2C19) metabolizes a number of clinically used drugs and shows a marked interethnic difference in the incidence of the poor metabolizer (PM). In the present study, we genotyped 215 healthy unrelated Koreans (64 females, aged 20-41 yr, residing in Chungcheong province) for functionally defective alleles, CYP2C19_(m1) and CYP2C19_(m2). Detection of the normal (CYP2C19_(wt)) and defective alleles was performed by polymerase chain reaction/restriction enzyme analysis. The genomic DNA was isolated from peripheral blood. The allelic frequencies of the wild-type (CYP2C19_(wt)) and CYP2C19_(m1) were 72.6% and 27.4%, and the wild-type (CYP2C19_(wt)) and CYP2C19_(m2) were 85.1% and 14.9%, respectively. For each CYP2C19_(m1) and CYP2C19_(m2), the observed numbers of three genotypes were similar to those calculated in accordance with the Hardy-Weinberg equation. The frequencies of homozygotes for CYP2C19_(m1), CYP2C19_(m2) and compound heterozygotes were 9.7%, 2.8% and 4.2%, respectively. The mutants of CYP2C19 were identified in 36 subjects (16.7%). These results suggest that frequency of mutants of CYP2C19 in Koreans resembled the Orientals rather than Caucasians.

Aceclofenac 경구제제의 생물학적 동등성 연구

권준택,김형기,손동렬,염윤기 순천향의학연구소 2004 Journal of Soonchunhyang Medical Science Vol.10 No.1

The bioequivalence of generic aceclofenac(Anacle^(®), Korea Pharma Co.) tablet to the aceclofenac tablet(Arital^(®), DaeWoong Pharmaceutical Co.) as a reference drug. Single dose of 100 mg aceclofenac was administered to 20 healthy male volunteers in a balanced, randomized crossover design with a washout between the two study periods. Blood samples were collected up to 12 hours and plasma concentration of aceclofenac was measured by well validated reverse phase high-performance liquid chromatography. Pharmacokinetic parameters were analyzed by non-compartmental analysis and ANOVA test was used for the statistical analysis of parameters. No statistically significant formulation, period, or sequence effect was encountered. Ninety percent confidence intervals of log transformed C_(max) and AUC_(t) were comprised in the stipulated 0.80-1.25 range. These results suggest that test formulation of aceclofenac is bioequivalent with the reference, both formulations in 100 mg tablet.

한국인에서의 CYP2E1 유전자형

권준택,김형기,손동렬,염윤기 순천향의학연구소 2004 Journal of Soonchunhyang Medical Science Vol.10 No.1

Cytochrome P4502E1 (CYP2E1) is inducible by ethyl alcohol and activates procarcinogenic N-nitrosodimethylamine (NDMA), benzene, urethane and other lower molecular weight compound. CYP2E1 is also involved in metabolism of certain drugs, for example, alcohol, acetaminophen, tamoxifen, theophylline, fluorinated anesthetics, and chlorozoxazone. CYP2E1 activity was shown to be polymorphically distributed in humans and has been suggested to play a role in hepatocellular carcinoma and alcoholic related disorders. Although genetic predisposition to alcoholism and alcoholic liver disease has been reported, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. The aims of this study were to investigate the allelic frequency of CYP2E1 Rsa I polymorphism in Koreans. We investigated the frequency distribution of CYP2E1 Rsa I polymorphism in 212 unrelated healthy Koreans and 42 hepatocellular carcinoma patients. Detection of the CYP2E1 alleles was performed by polymerase chain reaction and restriction fragment length analysis. The genomic DNA was isolated from peripheral blood with conventional phenol: chloroform extraction method. The allelic frequencies of c1 and c2 in healthy volunteers were 0.85 and 0.15, respectively. The rare type (c2/c2) of CYP2E1 Rsa I polymorphism was 0.005 in healthy volunteers.

Simvastatin 정제의 생물학적 동등성 연구

김형기,권준택,손동렬,염윤기 순천향의학연구소 2004 Journal of Soonchunhyang Medical Science Vol.10 No.1

The bioequivalence of generic simvastatin tablet(Dongsung Pharmaceutical Co.) to the simvastatin tablet(Zocor^(®), MSD Korea Co.) as a reference drug. Single dose of 20 mg simvastatin was administered to 20 healthy male volunteers in a balanced, randomized crossover design with a washout between the two study periods. Blood samples were collected up to 12 hours and plasma concentration of simvastatin was measured by well validated LC-MS/MS. Pharmacokinetic parameters were analyzed by non-compartmental analysis and ANOVA test was used for the statistical analysis of parameters. No statistically significant formulation, period, or sequence effect was encountered. Ninety percent confidence intervals of log transformed C_(max) and AUC_(t) were comprised in the stipulated 0.80-1.25 range. These results suggest that test formulation of simvastatin is bioequivalent with the reference, both formulations in 20 mg tablet.

혈장 중 theophylline 분석법 확립 및 약동학적 연구

김형기,권준택,염윤기 순천향대학교 교수학습개발센터 2004 Journal of Soonchunhyang Medical Science Vol.10 No.3

배경 및 목적 : 치료적 약물농도 모니터링이나 약물 상호작용연구에 활용할 수 있는 빠르고 간단한 혈중 theophylline의 분석방법을 확립한다. 재료 및 방법 : 표준 혈장시료에 1N HCl 100 ㎕를 첨가하고 내부 표준물질 7-(β-hydroxy-propyl) theophylline (50 ㎍/ml) 50 ㎕를 첨가한후 diethyl ether를 이용하여 추출한 후 질소기류하에서 건조하여 이동상으로 재용해한 후 C18 reverse-phase column에 주입하여 280 nm의 자외선파장에서 HPLC system을 이용하여 검출하였다. 표준 혈장시료를 이용하여 일내- 일간 정밀성과 정확성, 회수율, 단기, 장기 안정성 및 냉해동 안정성을 평가하여 분석방법을 검증하였다. 결과 : 최소검출농도는 0.1 ㎍/ml로 10 ㎍/ml의 농도까지 직선성을 관찰할 수 있었으며 일내- 일간 정밀성과 정확성, 회수율 및 단기, 장기 안정성 및 냉해동 안정성 모두 CV%가 10 % 이내로 분석방법을 확립하였다. 결론 : 본 실험결과 theophylline의 치료적 약물농도 모니터링 및 약물상호작용에 관련된 연구에 활용할 수 있는 빠르고 간단한 분석방법을 확립하였다.

혈장 중 theophyline 분석법 확립 및 약동학적 연구

김형기,권준택,염윤기 순천향대학교 의학연구소 2004 Journal of Soonchunhyang Medical Science Vol.10 No.3

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S-mephenytoin 산화다형성의 검색 지표약물로서 omeprazole의 유용성

김형기,권준택 순천향의학연구소 1998 Journal of Soonchunhyang Medical Science Vol.4 No.1

Racemic mixture of mephenytoin has been used to measure the CYP2C19. However, mephenytoin is not available in Korea, and its sedative effect limits its use in Oriental population. The purpose of this study was to evaluate the usefulness of omeprazole as a probe drug for S-mephenytoin polymorphism. Single oral doses of mephenytoin or omeprazole were administered at lest 2 weeks apart to 123 and 93 healthy volunteers, respectively. The capacity of S-mephenytoin hydroxylation was measured using the amount of hydroxymephenytoin excreted in 8-hr urine after taking 100 mg of mephenytoin, and omeprazole hydroxylation activity was defined as log10 [omeprazole/hydroxyomeprazole] determined in plasma collected 2 hr after taking a 20 mg of omeprazole. Both methods separated poor metabolizer (PM) or extensive metabolizer (EM) phenotypes of polymorphism with complete concordance. But, omeprazole hydroxylation index does not correlated well (r²=0.108) with the log10 % hydroxymephenytoin excreted in EMs. The PMs identified by the log10 hydroxymephenytoin excreted were also assigned as PMs of omprazole with the antimode of 1.0. The results suggest that omeprazole appears to be a safe and convenient tool to identify the capacity of S-mephenytoin hydroxylation.

Fluoxetine 정제의 생물학적 동등성 시험

김형기,권준택,염윤기 순천향대학교 교수학습개발센터 2004 Journal of Soonchunhyang Medical Science Vol.10 No.3

The bioequivalence of generic fluoxetine tablet(Myungin Pharmaceutical Co.) to the fluoxetine tablet(Prozac^(ⓡ)), Lilly Korea Co.) as a reference drug. Single dose of 60 mg fluoxetine was administered to 24 healthy male volunteers in a balanced, randomized crossover design with a washout between the two study periods. Blood samples were collected up to 72 hours and plasma concentration of fluoxetine was measured by well validated HPLC. Pharmacokinetic parameters were analyzed by non-compartmental analysis and ANOVA test was used for the statistical analysis of parameters. No statistically significant formulation, period, or sequence effect was encountered. Ninety percent confidence intervals of log transformed C_(max) and AUC_(t) were comprised in the stipulated 0.80-1.25 range. These results suggest that test formulation of fluoxetine is bioequivalent with the reference, both formulations in 60 mg tablet.