TDM의 문제아 : 활성대사물, 유리약물 농도 및 약물 Enantiomers

신재국,Shin, Jae-Gook 대한임상약리학회 1995 臨床藥理學會誌 Vol.3 No.1

Pharmacokinetics of Procainamide and N-acetylprocainamide

장인진,신재국,신상구,박찬웅,임정규,Chang, In-Jin,Shin, Jae-Gook,Shin, Sang-Goo,Park, Chan-Woong,Lim, Jung-Kyoo The Korean Society of Pharmacology 1989 대한약리학잡지 Vol.25 No.1

Procainamide를 투여후 이 약물 및 활성형 대사산물인 N-acetylprocainamide (NAPA)의 약동학적 성상을 알아보기 위해 숫컷 성견 5마리에 procainamide 및 NAPA를 교차 투여하여 얻은 혈장농도 data를 2-compartmental model에 의해 약동학적 분석을 시행하여 다음과 같은 결과를 얻었다. 1. 10mg/kg의 procainamide를 1회 15분간 정주후 혈장 procainamide 농도변화는 명백한 분포기와 소실기를 보였으며 생성된 NAPA의 혈장농도는 시간경과에 따라 최고혈장농도는 $0.124{\mu}g/ml$ 이하이었으며 정주 직후 조직분포에 따른 혈장농도의 일시적으로 감소 후 증가하는 초기 dip 현상을 보였다. 2. Procainamide의 steady-state 분포용적(Vss) 및 central compartment volume (Vc)은 각각 $1.20{\pm}0.27\;L/kg$ 및 $0.36{\pm}0.08\;L/kg$ 이였으며 NAPA의 Vss및 Vd는 $1.21{\pm}0.21\;L/kg$ 및 $0.26{\pm}0.07\;L/kg$이었다. 3. Procainamide 및 NAPA의 청소율(Cl)은 각 $0.47{\pm}0.08\;L/kg/hr$와 $0.35{\pm}0.08\;L/kg/hr$ 이었으며 혈장 반감기$(t_{1/2{\beta}})$는 각각 2.85 및 2.77 시간이었다. 4. N-acetylation에 의한 Procainamide의 대사청소율은 $18.24{\pm}6.22\;ml/kg/hr$로 이는 전체 procainamide 청소율의 3.9%를 차지하였다. To evaluate disposition characteristics of procainamide and its active metabolite, N-acetylprocainamide (NAPA), cross-over study for procainamide and NAPA was performed in 5 male adult dogs. After single administration of 10 mg/kg procainamide over 15 minutes, the range of measured plasma NAPA concentrations during experimental period were 0.03 to 0.124 ug/ml and early 'dip' phenomenon was distinct on NAPA concentration to time curve in all 5 dogs. Volume of distribution (Vss) and central compartment volume (Vc) of procainamide were $1.20{\pm}0.27\;L/kg$ of body weight and $0.36{\pm}0.08\;L/kg$, respectively. Vss and Vc of NAPA were $1.21{\pm}0.21\;L/kg$ and $0.26{\pm}0.07\;L/kg$, respectively. Intercompartmental clearance (Clint) of procainamide was 3.44 L/kg/hr and that of NAPA was 1.62 L/kg/hr. Total body clearance (Cl) of procainamide and NAPA were $0.47{\pm}0.08$ and $0.35{\pm}0.08\;L/kg/hr$. The half-life $(t_{1/2{\beta}})$ of procainamide and NAPA were 2.85 hrs and 2.77 hrs, respectively. Metabolic clearance (Clm)of procainamide by N-acetylation was $18.24{\pm}6.22\;ml/kg/hr$, which corresponded to 3.9% of total procainamide clearance.

Effect of Cimetidine on Theophylline Disposition and Metabolic Pathways

장인진,이선희,신재국,신상구,박찬웅,Jang, In-Jin,Lee, Sun-Hee,Shin, Jae-Gook,Shin, Sang-Goo,Park, Chan-Woong The Korean Society of Pharmacology 1990 대한약리학잡지 Vol.26 No.1

Cimetidine이 theophylline의 약동학적 특성과 대사과정에 미치는 효과를 검토코자 6마리의 개를 대상으로 일주일간 정맥내 cimetidine(30mg/kg/day)투여 전후에 단일 용량의 정맥투여에 따른 theophylline의 약동학적 parameter 및 뇨중 theophylline 대사물 배설의 변화를 교차 실험을 통하여 관찰하였다. 대조실험에 비해 cimetidine투여후 theophylline의 청소율은 평균 31%(P<0.05)감소하였고 혈장반감기는 29%(P<0.01)연장되었다. 그러나 steady-state의 분포용적 및 혈장 단백 결합의 변화는 관찰할 수 없었다. Theophylline의 주 대사물인 3-methylxanthine, 1-methyluric acid 및 1,3-dimethyluric acid의 24시간 뇨증 배설량은 cimetidine투여후 모두 감소 하였으나 통계적으로 유의한 변화는 아니었으며 개별대사물의 배설 분획은 변화가 없었다. 이상의 결과로 부터 cimetidine이 theophylline의 demethylation과 8-hydroxylation대사과정 모두를 비선택적으로 억제함으로써 청소율을 감소시키고 반감기를 증가시킬 것으로 추정되었다. The effect of cimetidine on theophylline metabolism was examined in dogs. Single dose intravenous theophylline kinetic studies were performed in cross-over manner before and after one week intravenous cimetidine (30 mg/kg/day) treatment. Cimetidine decreased theophylline clearance by an average of 31% (p<0.05) and prolonged theophylline half-li fe by an average of 29% (p<0.01) compared to those in control peirods. However, steady-state volume of distribution and protein binding of theophylline were not changed significantly. Twenty-four hours urinary excretion of 3-methylxanthine, 1-methyluric acid and 1,3-dimethyluric acid, which are the major metabolites of theophylline, were all decreased after cimetidine treatment, whereas the excreted fractions of individual metabolites were unchanged by cimetidine. From the above data, it could be susggested that cimetidine decreases theophylline clearance and prolongs the half-life by non-specific inhibition of the demethylations and 8-hydroxylation pathways.

Procainamide와 그 대사산물(N-acetylprocainamide)의 약동학적 분석에 관한 연구

장인진(In-Jin Chang),신재국(Jae-Gook Shin),신상구(Sang-Goo Shin),박찬웅(Chan-Woong Park),임정규(Jung-Kyoo Lim) 대한약리학회 1989 대한약리학잡지 Vol.25 No.1

To evaluate disposition characteristics of procainamide and its active metabolite, N-acetylprocainamide (NAPA), cross-over study for procainamide and NAPA was performed in 5 male adult dogs. After single administration of 10 mg/kg procainamide over 15 minutes, the range of measured plasma NAPA concentrations during experimental period were 0.03 to 0.124 ug/ml and early dip phenomenon was distinct on NAPA concentration to time curve in all 5 dogs. Volume of distribution (Vss) and central compartment volume (Vc) of procainamide were 1.20 ± 0.27 L/kg of body weight and 0.36 ± 0.08 L/kg, respectively. Vss and Vc of NAPA were 1.21 ± 0.21 L/kg and 0.26 ± 0.07 L/kg, respectively. Intercompartmental clearance (Clint) of procainamide was 3.44 L/kg/hr and that of NAPA was 1.62 L/kg/hr. Total body clearance (Cl) of procainamide and NAPA were 0.47 ± 0.08 and 0.35 ± 0.08 L/kg/hr. The half-life (t_1/2β) of procainamide and NAPA were 2.85 hrs and 2.77 hrs, respectively. Metabolic clearance (Clm)of procainamide by N-acetylation was 18.24 ± 6.22 ml/kg/hr, which corresponded to 3.9% of total procainamide clearance. Procainamide를 투여후 이 약물 및 활성형 대사산물인 N-acetylprocainamide (NAPA)의 약동학적 성상을 알아보기 위해 숫컷 성견 5마리에 procainamide 및 NAPA를 교차 투여하여 얻은 혈장농도 data를 2-compartmental model에 의해 약동학적 분석을 시행하여 다음과 같은 결과를 얻었다. 1. 10mg/kg의 procainamide를 1회 15분간 정주후 혈장 procainamide 농도변화는 명백한 분포기와 소실기를 보였으며 생성된 NAPA의 혈장농도는 시간경과에 따라 최고혈장농도는 0.124μg/ml 이하이었으며 정주 직후 조직분포에 따른 혈장농도의 일시적으로 감소 후 증가하는 초기 dip 현상을 보였다. 2. Procainamide의 steady-state 분포용적(Vss) 및 central compartment volume (Vc)은 각각 1.20 ± 0.27 L/kg 및 0.36 ± 0.08 L/kg 이였으며 NAPA의 Vss및 Vd는 1.21 ± 0.21 L/kg 및 0.26 ± 0.07 L/kg이었다. 3. Procainamide 및 NAPA의 청소율(Cl)은 각 0.47 ± 0.08 L/kg/hr와 0.35 ± 0.08 L/kg/hr 이었으며 혈장 반감기(t_1/2β)는 각각 2.85 및 2.77 시간이었다. 4. N-acetylation에 의한 Procainamide의 대사청소율은 18.24 ± 6.22 ml/kg/hr로 이는 전체 procainamide 청소율의 3.9%를 차지하였다.

임상연구병동 자동병상배정 전문가시스템 개발

송승미,김종명,김종률,신재국,김은영,Song, Seung-Mi,Kim, Jong-Myoung,Ghim, Jong-Lyul,Shin, Jae-Gook,Kim, Eun-Young 대한임상약리학회 2012 臨床藥理學會誌 Vol.20 No.1

Background: Demands for complicated and long-term administration clinical trials have been increased since investigators actively involved in early stage clinical trials including first-in-human (FIH) trials. Research wards in our clinical trial center were mainly used for phase 1 trials. In order to perform several clinical trials simultaneously during a short period with a minimum number of rooms, beds, and equipment, staffs have to spend a lot of time for efficient operation of limited numbers of facilities. In this study, automated bed-allocation system was developed for efficient scheduling of the research ward based on clinical trial condition and status like experts. Methods: The system was developed based on clinical trial design, schedule, and the information on research bed and availability stored and updated in database (DB). Automatic assignment system was designed to find an optimal schedule according to the given information using expert rules and algorithms. The optimal solution can be visualized on Gantt chart using C# and Chart FX API. Results: The system was developed to demonstrate the schedule on color chart. It turned out to be well-designed to find an optimal schedule for bed allocation. The system also allows automatic updating of the schedule and information in the DB. Conclusion: Automated bed-allocation system developed in this study could save time and improve the efficiency for using space and equipment in clinical trial center. The system can be also applied to similar works or tasks in other fields.

Comparison of Enalapril Maleate Tablets on Bioavailability and the Time Course of Inhibition of Plasma Angiotensin-Converting Enzyme

장인진,장병수,신상구,신재국,노일근,이경훈,박찬웅,Jang, In-Jin,Jang, Byung-Soo,Shin, Sang-Goo,Shin, Jae-Gook,Rho, Il-Kun,Lee, Kyeong-Hun,Park, Chan-Woong The Korean Society of Pharmacology 1990 대한약리학잡지 Vol.26 No.2

국내 생산 enalapril maleate 10mg 제제 $(Beartec^{\circledR})$의 생물학적 동등성을 검토키위해, 원 제조원인 Merck사의 $Vasotec^{\circledR}$을 기준 제제로하여 12명의 건강한 남성지원자를 대상으로 10mg 1회 경구 투여 교차시험후 약동학적 성상, ACE활성억제의 경시적 변화 및 혈압 변동을 검토한 결과는 다음과 같다. 1. 혈장 enalapril 및 활성형 대사물인 enalaprilat의 생체이용율 지표들(AUC, Tmax 및 Cmax)의 평균치는 시험제제에서 enalapril의 최고 혈장농도 도달시간(Tmax)이 약 27%(0.21시간)지연되었을 뿐 타 지포는 대조제제에 대한 백분율 차이에 있어 ${\pm}20%$내외였다. 2. 혈장 enalapril및 enalaprilat의 생체 이용율 지표들은 분산 분석에 의해 두 제제간에 차이를 인지할 수 없었다. 3. 시험제제의 생체이용율 지표들은, 대조제제에 대한 백분율을 95% 신뢰구간 검정시, enalapril의 AUC 및 Tmax를 제외한 enalapril 및 enalaprilat의 모든 지표는 ${\pm}20%$ 내외의 결과를 보였다. 4. 두제제 투여후 ACE활성도는 enalaprilat 혈장농도 5-6ng/ml에서 50%의 억제를 보였으며, 투약 23시간까지의 활성억제 AUC는 차이가 없었다. 5. 두 제제 투여후 수축기 및 이완기 혈압은 투약 2시간 이후 유의한 감소를 보였으며 혈압 변동은 두제제간에 차이를 인지할 수 없었다. 이상의 실험 결과로 enalapril maleate의 국내 생산 generic product는 기준제제인 $Vasotec^{\circledR}$과 동등한 생물학적 동등성을 지니며 치료적 등가성을 보이는 제제로 판단하였다. Enalapril maleate tablets of two different producers were tested for bioequivalence. Enalapril is rapidly metabolized to an active metabolite, enalaprilat which inhibits angiotensin-converting enzyme (ACE). The pharmacokinetics of enalapril maleate and the time course of inhibition of plasma ACE activity after administration of the drugs were studied. Two single doses of 10mg each of enalapril maleate were administered orally to twelve male volunteers in a balanced, randomized, two-way crossover investigation. Plasma enalaprilat concentrations were determined over a 23-hour after the dose by enzyme inhibition assay and enalapril by the same method following in vitro hydrolysis. Urinary recoveries of enalapril and enalaprilat were determined for the calculation of renal clearance. Plasma ACE activity was determined by an enzyme assay. Peak plasma levels of enalapril were observed about 1 hour after the doses, and practically all enalapril had disappeared from plasma within 6 hour. Peak enalapril concentrations of both formulations were almost identical ($Vasotec^{\circledR}$, 61.38 ng/ml; $Beartec^{\circledR}$, 64.27 ng/ml). The values of the pharmacokinetic parameters of enalaprilat computed for $Vasotec^{\circledR}$ and $Beartec^{\circledR}$ tablets are presented in that order; area under the curve=330.63:320.96 $ng{\cdot}hr/ml$; peak concentration=38.63:39.43 ng/ml; time to peak=3.83:4.08 hour; elimination half-life=3.95:3.92 hours. No statistically significant difference was detected when area under the curve and all other parameters were compared. Using criteria of 95% confidence interval for the comparison of these parameters, only the upper limits of area under the curve and time to peak of enalapril were over 120%. All the parameters of enalaprilat were acceptable. Percent inhibition of plasma ACE to plasma enalaprilat concentration showed the sigmoid concentration-inhibition relationship. Time courses of plasma ACE inhibition after the administration of both formulations were quite similar. The formulations were found to be equivalent when compared on the premise that no significant difference was detected when pharmacokientic parameters and inhibition of ACE activity were compared, based on the confidence limits analysis.

일측 신절제술 후 Netilmicin의 약동학적 특성의 경시적 변화

민권식,손지홍,차인준,정재일,최성협,신재국,윤영란,Min, Kweon-Sik,Shon, Ji-Hong,Cha, In-June,Jung, Jae-Il,Choi, Sung-Hyup,Shin, Jae-Gook,Yoon, Young-Ran 대한임상약리학회 1999 臨床藥理學會誌 Vol.7 No.1

연구배경: 일측 신절제술 후 이를 보상하기 위하여 남은 일측신장은 형태학적, 기능적인 변화를 나타낸다. 본 연구에서는 일측 신절제에 따른 신기능 변화에 따른 약물소실의 변화를 평가하기 위하여 일측 신절제술을 시행한 환자에서 netilmicin의 약동학적 변화를 수술 후 3개월까지 경시적으로 분석하였다. 방 법: 수술 후 netilmicin을 투여 받는 42명 (27명 : 일측 신절제술, 15명 : 대조군, 신절제술이 아닌 비뇨기과적 수술)의 환자를 대상으로, $2.5{\pm}0.3\;mg/kg$의 netilmicin을 일일 2회 반복투여 후 수술 1일 전, 술 후 1일, 3일, 7일 그리고 술 후 3개월에는 1회 투여 수 각각 2회의 채혈을 실시하였다. 이로부터 측정한 혈장 netilmicin 농도를 PCNONLIN을 이용하여 1-compartment 모델에 적용하여 약동학적 파라메터들을 산출하였다. 결 과: 일측 신절제술 후 혈장 크레아티닌치의 증가가 전 연구 기간에 걸쳐 나타났으며, 크레아티닌 청소율은 전 연구 기간 동안에 술전에 비하여 감소된 것으로 나타났다. 한편, 일측 신절제 후 산출된 netilmic의 최고농도는 술전에 비하여 유의한 변화가 없었으나, 술 후 7일 째의 netilmicin 최저 농도는 술전의 값$(0.41{\pm}0.11\;mg/L)$에 비하여 2배 정도 증가하였고 이는 술 후 3개월에는 술전의 수치로 회복되었다. Netilimicin의 혈장 청소율은 수술 후 점차로 감소하여 술 후 7일 째에 술전에 비하여 $27.4{\pm}5.8%$ 감소하여 가장 큰 변화를 보였다. Netilmicin의 반감기는 연장되었으며 신절제 후 7일에 술전에 비하여 $48.7{\pm}9.5%$ 연장되어 가장 큰 변화를 보였다. 변화한 혈장 청소율과 반감기는 술 후 3개월 째에는 술전의 수치로 회복되었다. 일측 신절제 후 감소한 netilmicin의 청소율의 퍼센트 변화량은 혈장 creatinine 값과 유의한 상관관계를 나타내었으며 (r= 0.05, p<0.01), 크레아티닌 청소율과도 유의한 상관관계를 보였다(r=0.47, p<0.01). 결 론: 이상의 결과들은 정상적인 기능을 하고 있는 일측 신장을 절제할 경우 변화된 신기능으로 인해 약물소실이 수개월간 영향을 받을 수 있으므로 일측 신절제술 직후 주로 신장을 통해 배설되는 약물 혹은 활성 대사 물에 대해서는 주의깊게 관찰해야하며, 약동학적 지식을 이용한 개별화된 적정요법을 적용하는 것이 필수적인 것으로 사료된다. Background : After unilateral nephrectomy, one remained kidney adapts morphologically and functionally in order to compensate the loss of opposite kidney. In this study, pharmacokinetics of netilmicin were repeatedly estimated to evaluate the time course of the renal functional changes on drug excretion after unilateral nephrectomy. Methods : After single or multiple doses of netilmicin$(2.5{\pm}0.3\;mg/kg)$, two blood samples were drawn at 1 day before, 1, 3, 7 days and 3 months after operation in 42 subjects (27 patients with unilateral nephrectomy and 15 control patients with general urological operations). Pharmacokinetic parameters were estimated from nonlinear fittings of plasma netilmicin concentrations to one compartment model with using PCNONLIN. Results : The serum creatinine and creatinine clearance were significantly changed compared to those values before operation and to those of control subjects. Without any significant changes of extrapolated peak netilmicin concentrations, trough concentrations increased up to 2.0 folds of baseline level$(0.41{\pm}0.11mg/L)$ at 7days after unilateral nephrectomy. Total netilmicin clearance was gradually decreased and the plasma half-life was prolonged, and the maximum changes of them were observed at 7days after nephrectomy($27.4{\pm}5.8%\;and\;48.7{\pm}9.5%$ of baseline values $90.1{\pm}5.4\;ml/kg/hr$ and $2.6{\pm}0.2hr$, respectively). All these pharmcokinetic changes of netilmicin were recovered to the baseline value at 3 months. The percent changes of netilmicin clearance showed good correlation with the serum creatinine concentration(r=0.50, p<0.01) and creatinine clearance(r=0.47, p<0.01). Conclusions : These results suggest that the renal function on drug excretion seems to change till months later after unilateral nephrectomy of a functional kidney and the close monitoring of a drug and/or metabolite excreted largely by kidney should consider in the subject with very recent unilateral nephrectomy.

신장이식 환자에서 Rifampin과 Cyclosporine의 약동학적 상호작용

손지홍,윤영란,김경아,박지영,차인준,김양욱,김영훈,신재국,Shon, Ji-Hong,Yoon, Young-Ran,Kim, Kyoung-Ah,Park, Ji-Young,Cha, In-June,Kim, Yang-Wook,Kim, Young-Hoon,Shin, Jae-Gook 대한임상약리학회 2000 臨床藥理學會誌 Vol.8 No.1

Background: We present a case whose plasma cyclosporine concentrations were markedly decreased after adding antituberculosis medications. To assess the effect of rifampin on this pharmacokinetic interaction, we evaluated the pharmacokinetic changes of cyclosporine in kidney-transplanted patients with tuberculosis before and after withdrawing rifampin. Methods : Two separate full pharmacokinetic studies of cyclosporine were performed in four kidney recipients with tuberculosis before and one month after withdrawing rifampin from antituberculosis medications. Multiple blood samples were repeatedly drawn after morning oral dose of cyclosporine, and cyclosporine concentrations were determined by HPLC method. Pharmacokinetic parameters were estimated from noncompartmental method using $WinNonlin{\circledR}$ Results : After withdrawing rifampin, changing patterns of all pharmacokinetic parameters were consistent in all 4 subjects. Corrected Cmax and AUC estimated on the same 100mg dose basis were significantly increased from $291.1{\pm}54.1$ ng/ml to $950.7{\pm}174.7$ ng/ml and from $1483.1{\pm}92.0$ ng/ml ${\cdot}$ h to $6047.2{\pm}666.6$ ng /ml ${\cdot}$ hr, respectively (p<O.Ol). Total oral clearance (Cl/F) estimated during administration of rifampin ($19.8{\pm}3.5$ L/kg) was decreased to $6.0{\pm}0.9$ L/kg after withdrawing rifampin. However, the prolongation of halflife was not statistically significant $(6.1{\pm}1.7 hour vs)$ $10.6{\pm}1.1)$. Conclusions : These results strongly suggest that rifampin markedly decrease the plasma concentration of cyclosporine coadministered through pharmacokinetic interaction, and careful dose readjustment should be considered from frequent monitoring of plasma cyclosporine concentrations in patients taking both cyclosporine and antituberculosis medications including rifampin.

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.

Ketoprofen 전신투여후 활액내로의 분포 약동학 : 집단약동학적 분석

박지영,손정환,윤영란,손지홍,차인준,서승석,최장석,신재국,Park, Ji-Young,Sohn, Jeong-Hwan,Yoon, Young-Ran,Shon, Ji-Hong,Cha, In-June,Seo, Seung-Suk,Choi, Jang-Suk,Shin, Jae-Gook 대한임상약리학회 2001 臨床藥理學會誌 Vol.9 No.1

Background : The disposition kinetics of ketoprofen into synovial fluid was estimated to predict the time course of ketoprofen concentration in synovial fluid in patients with arthritis. Methods : After repeated oral doses of ketoprofen 100 mg twice daily, ketoprofen concentrations of plasma and synovial fluid were determined at steady-state by high performance liquid chromatography(HPLC) in 17 arthritic patients. Plasma pharmacokinetic parameters were estimated from one compartmental open model and the penetration pharmacokinetic parameters into synovial fluid were estimated from nonlinear fitting to the effect compartment model using $NONMEM^{\circledR}$. Results: At steady-state, the observed peak concentrations of plasma and synovial fluid were $4.6{\pm}3.2{\mu}g/ml\;and\;2.4{\pm}1.9{\mu}g/ml$ at 2 hours and 5 hours after the last dose, respectively. Plots of plasma ketoprofen concentration against synovial concentration showed anticlockwise hysteresis, suggesting the time delay in the distribution of ketoprofen into synovial fluid from plasma. The estimated average rate constant for the ketoprofen loss from synovial $fluid({\kappa}_{co})$ was $0.16\;h^{-1}$. From the simulation of ketoprofen concentration curves, the predicted $C_{max}$ of synovial fluid was corresponded to 76.6 % of the plasma $concentration(1.44\;{\mu}g/ml\;vs\;1.881{\mu}g/ml)$ and time lag of $T_{max}$ between both fluid spaces was estimated to 3.1 hours. Conclusions : These results suggest that the time course of ketoprofen concentration in synovial fluid is different from plasma concentration-time profile after systemic administration of ketoprofen. The effect compartment model approach appears to be useful to predict the kinetics of ketoprofen in synovial fluid from the plasma data.