Pharmacogenetic Relevance of Diazepam Metabolism in Human Liver Samples

손동렬,Sohn, Dong-Ryul Korean Society for Clinical Pharmacology and Thera 1994 臨床藥理學會誌 Vol.2 No.2

Background : It has been well documented that the disposition of diazepam may differ markedly between different individuals. There is evidence to suggest a possible association between the variability of N-demethylation of diazepam and the S-mephenytoin hydroxylase polymorphism. However, the pharmacogenetic relevance of other metabolic pathways of diazepam is obscure at present. Method : Fresh human liver samples (n=14) were obtained as an excess material removed during surgery on the liver. After preparing the microsomes, the kinetic parameters of S-mephenytoin 4-hydroxylase in human liver microsomes were assessed. Enzyme kinetic parameters were obtained for the formation of oxazepam, temazepam and demethyldiazepam. The ability of S-mephenytoin to inhibit the formation of the metabolites was determined by measuring the velocity of production of these metabolites from diazepam in human liver microsomes in the presence of mephenytoin. Results : After incubating with $200{\mu}M$ diazepam, the average velocities of formation of demethyldiazepam, temazepam and oxazepam in 14 different liver preparations were $11.3{\pm}5.9,\;23.7{\pm}16.9\;and\;1.5{\pm}1.1$pmole/mg protein per min, respectively. Among the individual Michaelis-Men-ten parameters of diazepam metabolism, only the $V_{max}$ of N-demethylation gave a close correlation $(r_s=0.821,\;p<0.05)$ with the $V_{max}$ of S-mephenytoin hydroxylation. Three liver samples showed a 9-fold smaller mean $V_{max}$ of diazepam demethylation than that of the remaining 11 samples. Conclusion : This study provided further evidence that S-mephenytoin 4-hydroxylase is primarily responsible for the formation of demethylation but not for the $C_3$-hydroxylation of diazepam in Korean liver samples. 배경: 개체 간에 다양한 반응을 보이는 diazepam의 대사는 N-demethylation, $C_3$-hydroxylation등의 경로에 의해 이루어지며, 대사정도에 의해 각 개체의 약물효과가 결정된다. 이들의 대사경로 중 N-demethylation과정은 in vivo 연구에서 약물유전학적으로 결정된 S-mephenytoin hydroxylase에 의해 이루어진다고 하나 그 외의 과정은 아직 규명되어 있지 않다. 방법 : 한국인의 간 조직을 이용하여 이들의 S-mephenytoin hydroxylation 능력을 결정 한 후 S-mephenytoin hydroxylation의 대사능력 에 따르는 diazepam의 대사산물인 demethyldiazepam, temazepam및 oxazepam의 형성되는 정도를 HPLC로 측정하였다. 결과 : 14례의 한국인 간 조직에서 $200{\mu}M$의 diazepam을 incubation시켰을 때 demethyldiazepam, temazepam 및 oxazepam의 평균 형성속도는 각각 $11.3{\pm}5.9,\;23.7{\pm}16.9\;and\;1.5{\pm}1.1$pmole/mg protein/min이었다. 각종 Michaelis-Menten 지수 중 N-demethylation의 $V_{max}$와 S-mephenytoin hydroxylation의 $V_{max}$만이 통계적으로 유의한 상관관계 $(r_{s}=0.821,\;p<0.05)$가 있었다. 14례의 간 조직 중 3례는 상대적으로 낮은 $V_{max}$ 및 높은 $K_{m}$을 보였고 이 조직들은 나머지 11례의 간 조직 보다 diazepam의 N-demethylation의 $V_{max}$가 1/9에 불과하였다. 결론 : Diazepam의 대사물질인 demethyldiazepam의 형성에 S-mephenytoin hydroxylase가 밀접한 관계가 있음이 분명하였으나 한국인 간 조직에서 diazepam의 $C_{3}$-hydroxylation에는 다른 효소가 관여할 것으로 사료된다.

GS354 and GS389: New Type of Calcium Channel Blockers

장기철,손동렬,정원석,정수연,이영수,김시환,노홍기,서정서,다까자와,가라끼,Chang, Ki-Churl,Sohn, Dong-Ryul,Chong, Won-Seog,Chung, Soo-Youn,Lee, Young-Soo,Kim, Si-Hwan,Noh, Hong-Kee,Suh, Joung-Seo,Takizawa, Satoko,Karaki, Hideaki The Korean Society of Pharmacology 1991 대한약리학잡지 Vol.27 No.1

GS354와 GS389의 세포내 칼슘{$[Ca^{2+}]_{1}:$ Fura-2의 형광으로 측정}과 근장력 변화에 대하여 백서의 흉부동맥을 사용하여 검토하였다. GS354와 GS389 모두 고농도의 포타슘과 노어에피네프린에 의한 수축을 억제시켰다. GS354의 헐관이완은 $[Ca^{2+}]_{1}$의 감소가 동반되었고 고농도의 포타슘에 의한 $[Ca^{2+}]_{1}$증가억제 현상도 칼슘통로 활성제인 Bay K8644에 의하여 길항되었다. 그러나 혈관이완 작용은 Bay K8644에 의해 억제 되지 않았다. 이러한 사실은 GS354는 칼슘통로를 차단하여 $[Ca^{2+}]_{1}$을 감소시키며 또한 수축기구에 대한 칼슘의 감수성을 낮추는 것을 암시하는 결과이다. 한편 GS389는 세포내 형광성을 증가시켰으나 이것은 Fura-2에 의한 형광이 아니라 내인성 피리딘 뉴클레오타이드에 의한 것으로서 나타났다. 이것은 미토콘드리아 기능을 억제하는 것을 의미하며 이러한 현상때문에 GS389에 대한 $[Ca^{2+}]_{1}$의 측정이 곤란하였으나 계속하여 Bay K8644를 첨가하여 본 결과 형광은 더욱 증가 되었으나 혈관이완은 역전되지 않았다. 이러한 사실은 GS389가 칼슘통로를 억제하며 아울러 수축기구에 대한 칼슘의 감수성을 낮추는 것을 암시하는 결과로 사료된다. The inhibitory effects of GS354 and GS389 on cytosolic $Ca^{2+}$ level ($[Ca^{2+}]_{1}$; measured with fura-2 fluorescence) and muscle tension in vascular smooth muscle of rat thoracic aorta were investigated. Both GS354 and GS389 inhibited the contractions induced by high $K^+$ or by norepinephrine. The vasodilator effect of GS354 was accompanied by a decrease in $[Ca^{2+}]_{1}$. The inhibitory effect on high $K^+-stimulated$ $[Ca^{2+}]_{1}$ was antagonized by a $Ca^{2+}$ channel activator, Bay K8644. However, the inhibitory effect on muscle tension was not antagonized by Bay K8644. These results suggest that GS354 inhibits $Ca^{2+}$ channels to decrease $[Ca^{2+}]_{1}$ and also decreases $Ca^{2+}$ sensitivity of contractile elements. The inhibitory effects of GS389 was accompanied by the increase in tissue fluorescence. This increment was not due to fura-2 fluorescence but to endogeneous pyridine nucleotides, suggesting that GS389 has an effect to inhibit mitochondrial function. Because of this interference, effects of GS389 on $[Ca^{2+}]_{1}$ was obscured. However, since sequential addition of Bay K8644 in the presence of GS389 further increased the fluorescence but not muscle tension, this compound seems to have the effects to inhibit $Ca^{2+}$ channels and to decrease $Ca^{2+}$ sensitivity of contractile elements.

Aceclofenac 경구제제인 에이서정의 생물학적동등성에 관한 연구

김동현,신경수,손동렬,Kim, Dong-Hyun,Shin, Kyung-Sue,Sohn, Dong-Ryul 대한임상약리학회 2001 臨床藥理學會誌 Vol.9 No.2

Background : The bioavailability of a generic preparation of aceclofenac(Acer from Kyungdong Pharmaceutical Company) was evaluated in comparison with a proprietary product(Airtal from Daewoong Pharmaceutical Company). Methods : Sixteen healthy male volunteers participated in the study conducted according to a two-way crossover, open-labeled Latin square design. The bioavailability was compared using the parameters total area under the plasma concentration-time curve$(AUC_{0-{\infty}})$, peak plasma concentration$(C_{max})$ and time to reach peak plasma concentration$(T_{max})$. Results : No statiscally significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic-transformed $AUC_{0-{\infty}}\;and\;C_{max}$ values of Acer over those of Airtal was found to lie between 0.94-1.03 and 0.94-1.06, respectively, being within the acceptable bioequivalence limit of 0.80-1.25. Conclusion : These findings indicate that the two preparations are comparable in the extent and rate of absorption.

GS354, GS389: 새로운 칼슘 길항제

장기철(Ki Churl Chang),손동렬(Dong-Ryul Sohn),정원석(Won Seog Chong),정수연(Soo Youn Chung),이영수(Young Soo Lee),김시환(Si Hwan Kim),노홍기(Hong Kee Noh),서정서(Joung Seo Suh),다까자와(Satoko Takizawa),가라끼(Hideaki Karaki) 대한약리학회 1991 대한약리학잡지 Vol.27 No.1

The inhibitory effects of GS354 and GS389 on cytosolic Ca²⁺ level ([Ca²⁺]₁; measured with fura-2 fluorescence) and muscle tension in vascular smooth muscle of rat thoracic aorta were investigated. Both GS354 and GS389 inhibited the contractions induced by high K⁺ or by norepinephrine. The vasodilator effect of GS354 was accompanied by a decrease in [Ca²⁺]₁. The inhibitory effect on high K⁺-stimulated [Ca²⁺]₁ was antagonized by a Ca²⁺ channel activator, Bay K8644. However, the inhibitory effect on muscle tension was not antagonized by Bay K8644. These results suggest that GS354 inhibits Ca²⁺ channels to decrease [Ca²⁺]₁ and also decreases Ca²⁺ sensitivity of contractile elements. The inhibitory effects of GS389 was accompanied by the increase in tissue fluorescence. This increment was not due to fura-2 fluorescence but to endogeneous pyridine nucleotides, suggesting that GS389 has an effect to inhibit mitochondrial function. Because of this interference, effects of GS389 on [Ca²⁺]₁ was obscured. However, since sequential addition of Bay K8644 in the presence of GS389 further increased the fluorescence but not muscle tension, this compound seems to have the effects to inhibit Ca²⁺ channels and to decrease Ca²⁺ sensitivity of contractile elements. GS354와 GS389의 세포내 칼슘{[Ca²⁺]₁: Fura-2의 형광으로 측정}과 근장력 변화에 대하여 백서의 흉부동맥을 사용하여 검토하였다. GS354와 GS389 모두 고농도의 포타슘과 노어에피네프린에 의한 수축을 억제시켰다. GS354의 헐관이완은 [Ca²⁺]₁의 감소가 동반되었고 고농도의 포타슘에 의한 [Ca²⁺]₁증가억제 현상도 칼슘통로 활성제인 Bay K8644에 의하여 길항되었다. 그러나 혈관이완 작용은 Bay K8644에 의해 억제 되지 않았다. 이러한 사실은 GS354는 칼슘통로를 차단하여 [Ca²⁺]₁을 감소시키며 또한 수축기구에 대한 칼슘의 감수성을 낮추는 것을 암시하는 결과이다. 한편 GS389는 세포내 형광성을 증가시켰으나 이것은 Fura-2에 의한 형광이 아니라 내인성 피리딘 뉴클레오타이드에 의한 것으로서 나타났다. 이것은 미토콘드리아 기능을 억제하는 것을 의미하며 이러한 현상때문에 GS389에 대한 [Ca²⁺]₁의 측정이 곤란하였으나 계속하여 Bay K8644를 첨가하여 본 결과 형광은 더욱 증가 되었으나 혈관이완은 역전되지 않았다. 이러한 사실은 GS389가 칼슘통로를 억제하며 아울러 수축기구에 대한 칼슘의 감수성을 낮추는 것을 암시하는 결과로 사료된다.

염산티로프라미드제제의 생물학적 동등성 평가

명승운(Seung Woon Myung),김동현(Dong Hyun Kim),김명수(Myung Soo Kim),강태경(Tae Kyeong Kang),민혜기(Hye Ki Min),장윤정(Yoon Jung Jang),손동렬(Dong Ryul Sohn),홍영훈(Young Hun Hong),신창식(Chang Shik Shin) 한국응용약물학회 2000 Biomolecules & Therapeutics(구 응용약물학회지) Vol.8 No.3

The bioequivalence of two tiropramide products was evaluated in 18 health male volunteers following oral administration. Test product was Tiram^R tablet (Shin Poong SP-102) (Shin Poong Pharm. Co., Ltd.) and reference product was Tiropa^R tablet (Dae Woong Pharm. Co., Ltd.) One capsule of the test and reference product containing 100 mg of tropramide · hydrochloride was administered to the volunteers by randomized two period cross-over study (2 X 2 Latin square method). The drug concentration in plasma was determined by GC/MS for over a period of 12hours after administration. Analysis of variance reveal that there are no differences in AUC (area under the plasma concentration-time curve from time zero to infinity), Cmax (maximum plasma concentration) and Tmax (time to reach Cmax). The differences of mean AUC, Cmax and Tmax between two products were 3.85, 1.47 and -3.6%, respectively. Minimum detectable differences (%) at α=0.1 were all less than 20% given as a guideline (18.07, 17.00 and 20.69% for AUC, Cmax and Tmax, respectively) . From these results, the two products are bioequivalent.

티로프라미드 주사제의 생물학적 동등성 평가를 위한 GC/MS 방법

명승운(Seung-Woon Myung),김명수(Myungsoo Kim),김혜영(Hye-Young Kim),곽현태(Hyun-Tae Kwak),민혜기(Hye-Ki Min),손동렬(Dong-Ryul Sohn),홍영훈(Young-Hun Hong) 한국분석과학회 2001 분석과학 Vol.14 No.3

노인환자의 적정 약물요법

손동렬 순천향대학교 의학연구소 2009 Journal of Soonchunhyang Medical Science Vol.14 No.3

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신약의 개발과 임상시험

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

임상시험의 개요

孫東烈 대한의학협회 1995 대한의학협회지 Vol.38 No.6

약물 유해반응 보고지침 -임상시험의 안전성에 관한 정보 관리지침 -

지동현,김훈교,배진우,손동렬,김인범,전용관,박혜연 大韓臨床藥理學會 1998 臨床藥理學會誌 Vol.6 No.2