Effect of the Intravenous Time , and the Rate and Composition of Fluid Replacement on the Pharmacokinetics and Pharmacodynamics of the Same Total Dose of Intravenous Furosemide

Lee, Myung Gull 한국약제학회 1986 Journal of Pharmaceutical Investigation Vol.16 No.4

The pharmacokinetics and pharmacodynamics of furosemide were evaluated after intravenous administration of the same total dose of furosemide in different lengths of infusion time (10 seconds, 30 min, 2 and 8 hr) to six dogs. The fluid loss in urine was immediately replaced volume for volume with intravenous infusion of lactated Ringer's solution. The pharmacokinetic parameters such as percent of the dose excreted in urine, total body and renal clearances, and terminal half-life were not significantly different with 4 different infusion times. The volume of distribution at steady state and mean residence time based on venous data, on the other hand, appeared to increase with increasing infusion time. The mean values for Vss were 0.334, 0.478, 0.499 and 0.708 1/㎏ for 10 seconds, 30 min, 2 hr and 8 hr of infusion, respectively and the corresponding values for MRT were 17.5, 22.2, 24.8 and 38.1 min. The diuretic effects (urine output and urinary excretion of sodium) were generally found to increase with increasing infusion times; the total mean 24 hr urine outputs were 1,102, 1,464, 2,190 and 3,470 ㎖ for 10 seconds, 30 min, 2 hr and 8 hr or infusion, respectively, and the corresponding values for sodium excretion were 170, 175, 272, and 440 mmol. Furosemide plasma concentrations and hourly urinary excretion rates of furosemide, sodium and potassium during the apparent steady state (between 2-8 hr) in the 8 hr infusion study were fairly constant. Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using dog as a model animal. Each of 6 dogs rececived 8-hr constant intravenous infusion of 20㎎(15㎎ used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II ) and 100 replacement (treatment III) with lactated Ringer's solution as well as with 100 replacement with 5% dextrose in water (treatment IV). Most of pharmacokinetic parameters such as plasma clearance, steady state volume of distribution, mean residence time and terminal half life were essentially the same in all 4 treatments. Renal clearances and urinary excretion rates of the drug in treatments II, III and IV were essentially the same, but about 20% higher than those in treatment I. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were, however, markedly different among the 4 treatments. For example, mean 10 hr urine outputs were 646, 1,046, 3,156 and 1,976 ㎖and mean 10 hr sodium excretions were 87.0, 142, 383 and 97.2 mmol for treatments I-IV, respectively. Except for treatment III, diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that (a) no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis indicating the insignificance of water compensation in tolerance development; (b) in treatment II where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition: (c) at steady state the hourly diuresis and natriuresis could differ up to about 10 times between treatments. Some implications in kinetic/dynamic relationship or modeling, in the clinical use and in the bioequivalency evaluation of dosage forms are discussed. 정제는 모든 제형중 가장 사용빈도가 높으면서도 거의 경험적으로 제제설계 등이 개선되어 왔으나 T. Higuchi 및 C. Fuhrer에 의해 정제기에 나타나는 타정압과 타정력을 측정할 수 있는 전기적 측정장치가 개발되고 그 결과 타정과정의 물리화학적인 mechanism이 규명되기 시작하였다. 이 방면 연구의 진행결과 항상 정제내 입자의 배열(preferred orientation of particles)이라는 문제점을 부각시켰다. 입자의 방향성(anisometry)은 약물에서 자주 관찰되는 침상입자나 葉狀입자에서 특히 두드러진다. 이러한 침상입자나 葉狀입자는 die중에서 배열되기 쉬우며 따라서 이들 입자로 정제자체도 방향성을 띄게 된다. 타정 중 흔히 나타나는 장해인 capping의 원인으로는 일반적으로 die중에 충전된 약물 중에 함유되어 있는 공기의 배출이 신속하지 못한 것으로만 알려져 왔으나 die중에 충전된 약물입자의 층상배열에 의한 방향성도 다른 하나의 원인이 된다고 추론되었다. 정제는 타정 중 심한 변형을 강요당한 수많은 입지로 구성되기 때문에 현미경으로는 입자의 배열을 관찰하기 힘들다. 반면 전자현미경으로는 입자의 배열을 관찰할 수 있으나 정성적인 연구가 가능할 뿐 정량적인 연구는 불가능하다. x-ray crystalloraphy를 이용한 정제 내 입자의 배열에 관한 연구가 보고된 바 있으나 모두 정성적이거나 반정량적 차원에 머물은 바 저자는 이를 정량적으로 연구하는 방법론과 타정중의 mechanism을 규명하려 시도하였다. 사용물질로는 polymorphism을 나타내지 않거나 타정중 polymorphism의 modification이 변형되지 않는 acetylsalicylic acid, phenacetin, paracetamol, tolbutamide, salicylic acid를 첨가물을 가하지 않고 일정 입자형으로 사분하여 eccentric 형 정제기에서 타정하였으며 또한 타정압을 측정하였다. 사용물질 중 acetylsalicylic acid와 salicylic acid는 침상, phenacetin은 葉狀, tolbutamide와 paracetamol은 다소의 방향성을 띄었다. 사용물질을 ball mill로 분쇄시켜 구형상의 입자를 얻었으며 이 구형상의 입자를 등방성(isometry), 즉 random 배열의 model로 삼았다. 정제 내 입자배열을 표현하는 방법으로 D. Train, J.W. Shell, Y. Nakai 등이 제안한 방법들이 있는 바, 1. x-ray crystallogram 상의 주 peak로 2. x-ray crystallogram 상의 주 peak를 전 peak의 합에 대한 비로, 3. x-ray crystallogram 상의 주 peak를 임의로 선택한 다른 한 peak에 대한 비로 각각 표시하였다. 저자는 상기 표현방법들이 본 연구에 적합치 않다고 판단한 바, 새로운 표현방법을 사용하였다. 따라서 저자는 정제 tkdas, 하면과 정제를 수직으로 절단한 면을 teleprint와 computer를 연결한 powder deffractometer x-ray crystallography와 전자현미경을 이용하여 측정, 비교하여 입자나 정제내에서 어느 방향으로 배열하는가와 또한 정제 상·하면의 입자의 배열상태를 연구하였고 정제를 정제상면에 평행하게 층상으로 얇게 잘라 측정하여 정제내부의 배열상태를 연구하였으며 정제의 hardness를 수직방향과 수평방향으로 측정하여 (정제강도의 방향성) 정제의 수직방향과 수평방향에서의 배열상태 (입자배열의 방향성)와의 相關性을 考察하였다. 또한 particle shape가 정제 구성에 미치는 영향을 연구하기 위하여 사용물질들을 다양한 crystal form으로 재결정시켜 타정하고 상기과 같이 연구하였다.

Pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidine-7-one (DA-8159) and nitroglycerin in rats

Lee, Shin Jung,Bae, Soo Kyung,Lee, Myung Gull,Kwon, Jong Won,You, Moohi,Lee, Duk Chul Wiley (Blackwell Publishing) 2005 Journal of pharmacy and pharmacology Vol.57 No.11

Hepatobiliary Excretion of Tributylmethylamonium in Rats with Lipopolysaccharide-Induced Acute Inflammation

Lee, In-Kyung,Lee, Young-Mi,Song, Im-Sook,Chung, Suk-Jae,Kim, Sang-Geon,Lee, Myung-Gull,Shim, Chang-Koo The Pharmaceutical Society of Korea 2002 Archives of Pharmacal Research Vol.25 No.6

The alteration in the pharmacokinetic behaviors of organic cations (OCs) in rats during acute inflammation (AI) was investigated. AI was induced by an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) 24 hr prior to the start of pharmacokinetic studies. Tributylmethylammonium (TBuMA) was selected as a model OC since it is largely excreted into bile, and is neither metabolized nor binds to proteins in the body. When TBuMA was administered intravenously to AI rats at a dose of 6.6 $\mu$mole/kg, the AUC was increased, while biliary excretion (i.e., cumulative amount and apparent clearance) was decreased compared to normal rats. When TBuMA was administered intravenously to AI rats at a constant rate (i.e., a bolus injection at a dose of 1.5 $\mu$mole/kg followed by a constant infusion at a rate of 1.5 $\mu$mole/kg/hr for 165 min), steady-state concentrations of plasma and liver concentrations of TBuMA were increased significantly, while in vivo hepatic uptake (amount) and canalicular excretion (clearance) were decreased. These results are consistent with a hypothesis in which both the sinusoidal uptake of TBuMA into hepatocytes via the OCT1 and the canalicular excretion of the compound from hepatocytes via the P-gp are decreased by LPS-induced AI.

HPLC Analysis, Stability, Blood Partition, Protein Binding, and Dose-independent Pharmacokinetics of KR-31543, a New Neuroprotective Agent for Ischemia-reperfusion Damage

Lee Myung Gull,Lee MiHye,Kim EunJung,Kim YoonGyoon,Kim Sun-Ok,Lee Dong-Ha,Lim Hong,Yoo Sung-Eun 大韓藥學會 2001 大韓藥學會 總會 및 學術大會 Vol.2001 No.2

Importance of Plasma Globulin Binding of Azosemide for Diuretic Effects in Analbuminemic Rats

Lee Myung Gull,Kim Sang Geon,Kim SoHee,Lee AeKyung,Kim EunJung 大韓藥學會 2001 大韓藥學會 總會 및 學術大會 Vol.2001 No.2

로그변환 모델에 따른 생물학적 동등성 판정 연구

이영주(Young Joo Lee),김윤균(Yoon Goon Kim),이명걸(Myung Gull Lee),정석재(Suk Jae Chung),이민화(Min Hwa Lee),심창구(Chang Koo Shim) 대한약학회 2000 약학회지 Vol.44 No.4

Logarithmic transformation of pharmacokinetic parameters is routinely used in bioequivalence studies based on pharmacokinetic and statistical grounds by the United States Food and Drug Administration (FDA), European Committee for Proprietary Medicinal Products (CPMP), and Japanese National Institute of Health and Science (NIHS). Although it has not yet been recommended by the Korea Food and Drug Administration (KFDA), its use is becoming increasingly necessary in order to harmonize with international standards. In the present study, statistical procedures for the analysis of a bioequivalence based on the log transformation and a related SAS procedure were demonstrated in order to aid the understanding and application. The AUC parameters used in this demonstration were taken from the previous bioequivalence study for two aceclofenac tablets, which were performed in a single-dose crossover design. Analysis of variance (ANOVA), statistical power to detect 20% difference between the tablets, minimum detectable difference and confidence intervals were all assessed following log-transformation of the data. Bioequivalence of two aceclofenac tablets was then estimated based on the guideline of FDA. Considering the international effort for harmaonization of guidelines for bioequivalence tests, this approach may require a further evaluation for a future adaptation in the Korea Guidelines of Bioequivalence Tests (KGBT).

피하주사 및 국소도포시 [14C]DA-5018 의 약동력학

김원배(Won Bae Kim),양중익(Junn Ick Yang),이상득(Sang Deuk Lee),이응두(Eung Doo Lee),심현주(Hyun Joo Shim),이종진(Jong Jin Lee),이명걸(Myung Gull Lee) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.1

Pharmacokinetics of a new capsaicin analog, DA-5018 were evaluated after a subcutaneous injection or topical application of ^(14)C-labelled or unlabelled DA-5018 to rats and rabbits. After subcutaneous injection of ^(14)C-labelled or unlabelled DA-5018, 0.5 mg/kg (equivalent to DA-5018) to rats, the plasma total activity peaked at 2 hr with the terminal half life of 5.34 hr, however, unlabelled-DA-5018 peaked at 1 hr with the terminal half life of 1.26 hr. Moreover, the AUC (0.726 versus 0.233 ㎍ hr/ml) and MRT (7.82 versus 3.55 hr) increased significantly based on total radioactivity compared with intact DA-5018. Above data indicated that DA-5018 is extensively metabolized in rats and the terminal half- life of the metabolites) had a longer half-life than that of DA-5018. The cumulative percentages of biliary excretion of dose after subcutaneous injection of [^(14)C]DA-5018 was 40.2%, however, the value was only 2.14% when unlabelled DA-5018 was injected. After topical application of 0.1% or 0.3% ^(14)C-labelled or unlabelled DA-5018 cream, 500 mg/kg to rats, the plasma and tissue concentrations except applied skin were under the detection limit. After consecutive 7 days topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rats, the plasma concentrations were also under the detection limit. But the urinary excretion of DA-5018 was significantly increased by repeated topical administration. After topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rabbits, the plasma and urine concentrations were under the detection limit. Above data indicated that the skin permeation of DA5018 was lower and the metabolism of DA-5018 was higher in rabbits than that in rats.

Pharmacokinetic Changes in Drugs during Protein-Calorie Malnutrition: Correlation between Drug Metabolism and Hepatic Microsomal Cytochrome P450 Isozymes

Lee, Joo-Hyun,Suh, Ok-Kyung,Lee, Myung-Gull The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.7

The rats with protein-calorie malnutrition (PCM, 5% casein diet for a period of 4-week) were reported to exhibit 60 and 80% suppression in the hepatic microsomal cytochrome P450 (CYP) 1 A2 and CYP2C11 levels, respectively, and 40-50% decreases in CYP2E1 and CYP3A 1/2 levels compared to control (23% casein diet for a period of 4-week) based on Western blot analysis. In addition, Northern blot analysis showed that CYP1 A2, CYP2E1, CYP2C11, and CYP3A1/2 mRNAs decreased in the state of PCM as well. Hence, pharmacokinetic changes of the drugs in rats with PCM [especially the area under the plasma concentration-time curve from time zero to time infinity (AUC) changes of metabolite(s)] reported from literatures were tried to explain in terms of CYP isozyme changes in the rats. Otherwise, the time-averaged nonrenal clearance ($CL_{NR}$) of parent drug was compared. Pharmacokinetic changes of the drugs in other types of malnutritional state, such as kwashiorkor and marasmus, in both human and animal models were also compared. The drugs reviewed are as follows: diuretics, antibiotics, anticancer agents, antiepileptics, antiarrythmics, analgesics, xanthines, antimalarials, and miscellaneous.

Gas Chromatography - Nitrogen Phosphorous Selective Detection 을 이용한 혈장중 Haloperidol 및 대사체인 Reduced Haloperidol 의 동시정량

이민화,박경호,심창구,이명걸,박종세 한국약제학회 1992 Journal of Pharmaceutical Investigation Vol.22 No.3

A gas chromatographic method using nitrogen phosphorous selective detection was developed for simultaneous determination of haloperidol and its metabolite, reduced haloperidol, in human plasma. Combelen was used as internal standard. The method involved extraction and trimethylsilylation followed by the injection of 2-4 ㎕ of benzene layer, which was used to dissolve the trimethylsilylated derivatives of haloperidol and reduced haloperidol, onto SE-54 column [5% phenyl methyl silica fused capillary column, 16m×0.22 mm (I.D.)×0.33 μm (coated thickness)]. The temperature of column oven was programmed from 200℃ to 300℃ at the increase rate of 10℃/min, and also the temperatures of injector and detector were set at 300℃. Helium was used as carrier gas and its flow rate was maintained at 30 ml/min. The detection was conducted with nitrogen phosphorous selective detector. The retention times for combelen, reduced haloperidol and haloperidol were found to be 9.14, 9.75 and 9.99 min, respectively. The detection limits for haloperidol and reduced haloperidol in human plasma were both 0.2 ng/㎖. The coefficients of variation of the intra-assay were generally low (below 9.8%). The mean absolute recoveries of added haloperidol and reduced haloperidol from plasma were 72% and 84%, respectively. No interferences from endogenous substances were found.

3 ×3 라틴 방격법 모델에 따른 생물학적 동등성 시험의 통계 해석 : 온단세트론 제제에 대한 적용 예 Application to Bioequivalence Test of Ondansetron Formulations

이민화,이영주,심창구,정석재,이명걸 한국약제학회 1998 Journal of Pharmaceutical Investigation Vol.28 No.1

A 3×3 Latin square crossover study for the bioequivalence of three ondansetron formulations was conducted. Test products were Vominon^ⓡ 8 ㎎ and Vominon^ⓡ ㎎ tablets and reference product was Zofran^ⓡ tablet. Twenty one healthy Korean male subjects received each formulation at the ondansetron dose of 8 ㎎ and plasma concentrations of ondansetron were monitored by HPLC for over a period of 12 hr after the oral administration. Statistical procedure for bioequivalence evaluation of AUC {e.g., analysis of variance (ANOVA), multiple comparison and confidence intervals} was carried out. There were no significant differences in AUC among the formulations. The confidence intervals for the AUC of Vominon^ⓡ 8 ㎎ and Vominon^ⓡ 4 ㎎ were between -0.24 and 15.54% and between -2.41 and 13.36% respectively, within a range that proposed by the Korea Food and Drug Administration Guidelines for Bioequivalence. These statistical procedure could be standardized and generally applicable for the assessment of bioequivalence for multiple (more than two) formulations.