만성 간질환 환자에서 Metoprolol의 약동학에 관한 연구

채희복,이경훈,차영남,이영상,서동진,윤영란,신재국,임동석,신상구,장인진,Chae, Hee-Bok,Lee, Kyung-Hoon,Cha, Young-Nam,Lee, Young-Sang,Suh, Dong-Jin,Yoon, Young-Ran,Shin, Jae-Gook,Yim, Dong-Seok,Shin, Sang-Goo,Jang, In-Jin 대한임상약리학회 1999 臨床藥理學會誌 Vol.7 No.1

연구배경 : 간기능은 심하게 진행되기 전까지는 단백합성기능, 배설기능, 약물대사기능 등이 잘 보존되며, 고추출율 약물은 저추출율 약물에 비해 약물 대사능과 간기능의 장애 정도간에 더 밀접한 상관관계가 있음이 알려져 있다. 선택적 ${\beta}_1$-adrenoceptor 길항제인 metoprolol은 주로 간에서 대사되며 경구투여시 1차통과효과(first pass effect)가 큰 고추출율 약물로, metoprolol의 ${\alpha}$-수산화 대사는 간장의 CYP2D6 활성도를 측정하는데 이용되고 있다. 따라서 본 연구에서는 비교적 진행된 간기능 장애를 지닌 modified Child-Pugh class B군과 C군에 해당하는 만성 간질환 환자에서 metoprolol 및 ${\alpha}-OH$ Metoprolol의 약동학적 성상을 대조군과 비교함으로써, 간기능 장애정도에 따른 약물대사능의 변화(특히 CYP2D6 활성도의 변화)를 규명하고자 하였다. 대상 및 방법 : 정상대조군 피험자 8명과 modified Child-Pugh class B군 9명 및 C군 7명을 대상으로, metoprolol 50 mg을 경구로 일회투여후 경시적으로 혈장과 요중 metoprolol 및 그 대사체인 ${\alpha}$-OH metoprolol의 농도를 관찰하였다. Metoprolol 및 ${\alpha}$-OH metoprolol의 혈장과 요중 농도는 형광검출기를 이용하여 HPLC로 측정하였으며, 약동학적 파라미터는 noncompartmental 분석법으로 산출하였다. 결과 : Metoprolol의 약동학적 변수중 $C_{max},\;T{max},\;t_{1/2{\beta}}$, $ACU_{0-12hr}$가 환자군과 대조군간에 통계적으로 유의한 차이를 나타내었으며 , ${\alpha}$-OH metoprolol에 대해서는 $C_{max}$와 $T_{max}$가 두 군간에 통계적으로 유의한 차이를 나타내었다. 환자들을 modified Child-Pugh class B군과 C군으로 나누어 비교시에는 약동학적 파라미터들에 차이가 없었다. 결 론 : 본 연구결과 정상대조군의 metoprolol 혈장농도곡 선하면적은 만성 간질환 환자군의 약 35%였으므로, 만성 간질환 환자에서 metoprolol의 초기용량은 정상인의 약 3분의 1 용량으로 시작하고 유지용량은 각 환자의 임상반응에 따라 조정하는 것이 바람직할 것으로 사료된다. Background : Metoprolol, the selective ${\beta}_1$-adrenoceptor antagonist, is eliminated primarily by hepatic metabolism. Usually less than 5% of an oral dose is excreted unchanged in the urine. Metoprolol is a highly extracted drug and its ${\alpha}$-hydroxylation pathway is mediated by CYP2D6. Therefore, it is often used as a probe drug to measure the metabolic capacity of liver. Method : The effects of impaired liver function on the pharmacokinetics of metoprolol were studied in 16 patients with hepatic cirrhosis (modified Child-Pugh class B and C group : 9 and 7 persons, respectively) together with 8 healthy volunteers. Pharmacokinetic parameters in these patients were compared to those in normal subjects. All subjects were given single oral doses of 50mg in the morning fasting state. Blood and urine samples were collected serially. The concentrations of metoprolol and ${\alpha}$-OH metoprolol in the biological fluids were measured by high-performance liquid chromatography using fluorescence detector. Results : There were statistically significant differences in $C_{max},\;T_{max},\;t_{1/2{\beta}}$, and $AUC_{0-12hr}$ of metoprolol between the patients and the normal subjects (p<0.05), ${\alpha}$-OH metoprolol produced by CYP2D6 was also measured and significant differences in both $C_{max}$ and $T_{max}$ were observed. There was no statistically significant difference in pharmacokinetic parameters between modified Child-pugh class B and C groups. Conclusion : For the sake of safety, the reasonable initial dose of metoprolol for the patients with portocaval shunts or advanced liver disease would be about one third of the usual dose, although the potential for adverse reactions is tempered by the flat dose response curve and the wide therapeutic index of this drug.

약인간염의 치료

채희복 ( Hee Bok Chae ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Drug induced liver injury (DILI) is both diverse and complex. Most DILI patients experienced mild elevation of aminotransferases and recovered even if they took the medicine continuously. Some DILI may lead to severe hepatitis with a risk of death. Therefore, adequate initial management after achieving an accurate diagnosis is important for physicians. Establishment of a worldwide network for monitoring the adverse events of drugs a universal diagnostic system for DILI are important for accurate diagnosis, and may lead to better management of DILI.

약인간염의 치료

채희복 ( Hee Bok Chae ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Drug induced liver injury (DILI) is both diverse and complex. Most DILI patients experienced mild elevation of aminotransferases and recovered even if they took the medicine continuously. Some DILI may lead to severe hepatitis with a risk of death. Therefore, adequate initial management after achieving an accurate diagnosis is important for physicians. Establishment of a worldwide network for monitoring the adverse events of drugs a universal diagnostic system for DILI are important for accurate diagnosis, and may lead to better management of DILI.

Portal Vein Thrombosis (2021 AASLD Guidance)

채희복 ( Hee Bok Chae ) 대한간학회 2021 간학회 싱글토픽 심포지움 Vol.2021 No.2

포스터 발표 : 간 ; 알코올과 CCl4 동시투여에 의한 간경변증 유도와 저용량 LPS의 간손상 보호효과

채희복 ( Hee Bok Chae ),박선미 ( Seon Mee Park ),윤세진 ( Sei Jin Youn ),장이찬 ( Lee Chan Jang ),최재운 ( Jae Woon Choi ),성노현 ( Ro Hyun Sung ) 대한소화기학회 2002 대한소화기학회 춘계학술대회 Vol.2002 No.-

〈목적〉 알코올과 CCl4를 동시에 투여할 때 간독성의 상승효과가 둘다 중심정맥부위에 괴시와 지방변성이 특징적이다. 두가지 약물을 투여하여 간경변이 유도되는 기간을 조사하여 보고자 하였다. 또한 저용량의 lipopolysaccharide(LPS)가 NO를 생산하여 간손상에 대한 세포보호효과가 있다고 Kamiya등이 보고한 바대로 동시에 위의 모델에 저용량의 LPS를 투여하여 그 효과를 알아 보고자 하였다. 〈방법〉 태령 5주된 250g 가량의 Sprag

알코올 간질환

채희복 ( Hee Bok Chae ) 대한소화기학회 2009 대한소화기학회지 Vol.53 No.5

A study conducted 15-year ago showed that only 13.5% of chronic alcoholics developed alcohol-induced liver damage, which misled some people to believe a lack of relationship between the amount of alcohol and the occurrence of liver disease. However, it is true that a significant correlation exists between per capita consumption and the prevalence of cirrhosis. Alcoholic fatty liver is observed in most of chronic alcoholics even though the severity is not uniform. Abstinence remains the cornerstone of therapy for alcoholic liver disease (ALD). There is also consensus for the use of corticosteroids and pentoxifylline in severe alcoholic hepatitis maintaining good nutritional status to treat comorbidities in all forms of ALD, and liver transplantation in the end-stage ALD patients who can stop drinking for 6 months pre-transplantation period. Several clinical trials targeting tumor necrosis factor (TNF-α) and reducing oxidative stress have not been successful at this time. There is still a large field of alcohol research to explore in order to go farther in the area of pathophysiology. We need to understand a role of various cytokines and immune cells in the development of ALD to have more treatment tools to cope with ALD. (Korean J Gastroenterol 2009;53:275-282)

림프구성 누두신경뇌사수체염 1 예

채희복(Hee Bok Chae),박중열(Joong Yeol Park),송영기(Young Ki Shong),김경조(Kyung Jo Kim),김철희(Chul Hee Kim),권병덕(Byoung Duk Kwun),최기영(Ghee Young Choe),황진복(Jin Bok Hwang),김기수(Ghi Su Kim) 대한내과학회 1997 대한내과학회지 Vol.52 No.3

Lymphocytic infundibuloneurohypphysitis(LINH) is a newly classified disorder and proposed as a common cause of idiopathic central diabetes insipidus. It is characterized by thickening of the infundibulum and/or pituitary stalk and absence of high signal in the neurohypophysis in sellar MRI and the microscopic findings of diffuse lymphocytic infiltration within the neurohypophysis. A 12year-old boy presented polyuria and headache. The result of water deprivation test was compatible with central diabetes insipidus. Brain MRI showed thickening of the pituitary stalk and loss of high signal in the neurohypophysis. Craniotomy and excisional bi6opsy was done under the impression of pituitary tumor. Microscopically, neurohypophysis showed dense lymphocytic infiltration and no malignant cells. Six months after the operation, the previously thickened pituitary stalk and neurohypophysis appeared normal in follow-up MRI.

Nimesulide에 의한 약제유발성 간염 1예

채희복(Hee Bok Chae),최원준(Won Jun Choi),이문우(Mun Woo Lee),박선미(Seon Mee Park),김혜영(Hye Young Kim),조명찬(Myeong Chan Cho),성노현(Ro Hyun Sung),윤세진(Sei Jin Youn) 대한내과학회 2000 대한내과학회지 Vol.59 No.1

Nimesulide, highly selective cyclooxygenase inhibitor-2, is a newly developed, non-steroidal anti-inflammatory drug (NSAID) with low toxicity in gastrointestinal tract. But recently, seven cases of nimesulide-induced hepatitis of which types were hepatocellular, hepatocanalicular, and mixed damage were reported. Our case of nimesulide-induced hepatic damage was mixed cholestatic and hepatotoxic hypersensititvity reaction, and her story was as follows. A 70-year female patient's first hepatic event happened in Jaunuary, 1998 after taking nimesulide 200mg daily for 50 days from November 1997, but it was cleared. She was admitted to our unit because of jaundice, edema and ascites in May, 1998 after retrial of nimesulide 150 mg daily for 50 days. Biochemical determinations showed increase of AST (181 IU/L), ALT (110 IU/L), bilirubin (20.3 mg/dL) and albumin (2.3 g/dL). Prothrombin time was also prolonged upto 2.51 INR. But neither viral markers such as anti-HCV, HBsAg, anti-HBc IgM, anti-HAV IgM, anti-CMV, anti-EBV IgG and IgM nor other immunologic markers such as ANA, SMA, and AMA were positive. Ultrasonography showed diffuse hyperechogenicity in liver and mild splenomegaly but no dilatation in biliary tract. Liver biopsy showed portal to portal bridging necrosis with severe hepatocytic cholestasis. Her liver function returned to normal after discontinuation of nimesulide. At 8 months after beginning treatment, she complained of recurrent epistaxis and abdominal distension. At this time, her liver biopsy showed cirrhosis. In conclusion, we considered that this case was nimesulide-induced Liver cirrhosis. (Korean J Med 59:114-119, 2000)

간 정맥폐쇄성 질환

채희복 ( Hee Bok Chae ),임정묵 ( Joung Muk Leem ),최재홍 ( Jae Hong Choi ),장이찬 ( Lee Chan Jang ),배일헌 ( Il Hun Bae ),성노현 ( Ro Hyun Sung ),윤세진 ( Sei Jin Youn ) 대한내과학회 2002 대한내과학회지 Vol.63 No.6

Veno-occlusive disease of the liver was first reported by Chiari in 1899. Pyrrolizidine-containing substances, chemotherapeutics and hepatic radiation injury can cause this disorder. Bone marrow and renal allograft recipients are at risk for the developme

새로운 만성C형간염 치료제 직접작용약제

채희복 ( Hee Bok Chae ) 대한소화기학회 2015 대한소화기학회지 Vol.66 No.1

Peg-interferon and ribavirin has been the standard therapy of chronic hepatitis C for the past 15 years in Korea. However, the treatment paradigm is changing. Direct acting agents (DAAs) are oral pills that can be easily taken. In addition, DAAs are more effective and have less adverse reactions compared to the previously used drugs. Chronic hepatitis C is hard to treat because the virus is error-prone virus. Host immunity is helpless against the hepatitis C virus since it evades the host immunity through various complex mechanisms. There are 6 genotypes. Quasispecies can co-exist even in the same patients. The treatment strategy is based on the combination of the individual drug corresponding to each step of viral replication process. NS5B nucleosides are the most powerful and effective drug available until now. Other drugs with different mechanisms of action can be used to provide synergy. NS5A and NS5B inhibition drugs currently belong to the leading group amongst many DAAs. These drugs will soon be available in Korea. We have to know the merits and adverse drug reactions of the new drug (Korean J Gastroenterol 2015;66:5-9)