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.

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

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

Pharmacokinetics of Methodtrexate after Intramuscular Injection of Methotrexate-Polysine Conjugate in Rabbits

Yoon, Eun-Jeong,Lee, Myung-Gull,Lee, Hee-Joo,Park, Man-Ki,Kim, Chung-Kook The Pharmaceutical Society of Korea 1990 Archives of Pharmacal Research Vol.13 No.2

Methotrexate (MTX)-poly-L-lysine (PLL) conjugate was relatively stable in phosphate buffer of pH 7.4 and in plasma. However, liver homogenate accelerated the release of MTX from the conjugate. Pharmacokinetics and tissue distribution of MTX were compared after intramuscular injection of MTX (treatment I) and MTX-PLL conjugate (treatment II), 10 mg/kg as free MTX to rabbits. The peak concentration of MTX in treatment II were significantly lower than those in treatment I. The amount of MTX excreted in 24-hr urine was significantly reduced in treatment II and it suggested that MTX be more metabolized in treatment II than in treatment I. The amounts of MTX remaining in each organ after 24-hr of intramuscular injection were not significantly different in both treatments.

Preparation and In vitro Release Characteristics of Hydrophilic Albumin Microspheres Containing Methotrexate and Methotrexate-Human Serum Albumin Conjugates

Hwang, Sung-Joo,Lee, Myung Gull,Kim, Chong-Kook 충남대학교 약학대학 의약품개발연구소 1992 藥學論文集 Vol.8 No.-

Release characteristics of five different types of hydrophilic albumin microspheres (HAM) containing different ratios of methotrexate-albumin (MTX-HSA) conjugates to free MTX; l:0 (HAMC), 3:l (HAMC3F), 1:l (HAMCF), l:3 (HAMCF3) and 0:1 (HAMF) were investigated in the absence or presence of protease using dissolution tester. In all the HAMs studied except HAMC the MTX was released bi-exponentially in the absence of protease; an initial fast release period up to approximately 6 h, and thereafter the release rate was very much slower. The fast release of MTX from the HAMS(such as HAMC3F, HAMCF, HAMCF3 and HAMF) at the initial phase is probably due to the release of "physically associated" MTX on the surface and/or entrapped in the near inner surface of HAMs and the slow release at the second phase is due to the release of entrapped free MTX from the core of the HAMs. The initial rate constants were 7.2, 8.7, 8.5 and 5.9 times greater than the second rate constants for HAMF, HAMCF3, HAMCF and HAMC3F, respectively. MTX release from HAMC was very slow and mono-phasic. It was at most 2.2% of the total entrapped amount by 24 h. The protease accelerated the release of MTX from the HAMs. The percentages of MTX released from HAMs up to 24 h were l00, 89.0, 75.0, 66.0 and 6l.0% for HAMF, HAMCF3, HAMCF, HAMC3F and HAMC, respectively in the presence of protease and the corresponding values in the absence of protease were 30.2, l9.0, 10.0, 6.5 and 2.2%, respectively. In vitro release of MTX in the presence of protease varied according to the ratios of MTX-HSA conjugates to MTX; the data set from HAMF, HAMCF3 and HAMCF fits better to monophasic first-order profile more adequately than to zero-order profile, that of HAMC3F to mono-phasic zero-order, and that of HAMC to bi-phasic zero-order. Above results suggested that zero-order release rate can be achieved by adjusting the ratio of MTX-HSA conjugates to MTX in the preparation of HAMs such as HAMC3F.

In vitro Drug Release Characteristics of Methotrexate-Human Serum Albumin and 5-Fluorouracil-Acetic Acid Human Serum Albumin Conjugates

Kim, Chong-Kook,Lee, Myung-Gull,Park, Man-Ki-Heejoo,Lee, Hae-Jin,Kang, Hae-Jin The Pharmaceutical Society of Korea 1989 Archives of Pharmacal Research Vol.12 No.3

The release rates of methotrexate (MTX) from MTX-human serum albumin (HSA) conjugate, and 5-fluorouracil (5-FU) from 5-FU acetic acid (AA)-HSA conjugate were determined after incubation of the conjugates in various conditions. The concentrations of 5-FU released from the conjugate increased monoexponentially, however those of MTX increased biexponentially in all studies. It indicated that there are two distinct types of MTX-HSA linkage, weakly and tightly bound linkages. The release rates of 5-FU were lower than those of MTX in all studies indicating that the bond of 5-FU-AA-HSA conjugate is very stable, which is supported by the higher value of activation energy (39. 9 vs 10. 7 Kcal/mole) using Arrhenius equation. The release rates of MTX and 5 -FU from the conjugates increased with incubation temperatures. Proteolytic enzyme and liver homogenates accelerated significantly the release rates of MTX and 5-FU. Approximately 1.30 and 22.0% of MTX were released after 12 hours of incubation in the absence and presence of protease, respectively. The corresponding values for 5-FU were released after 12 hours of incubation with rat liver homogenates which were diluted 6 times with phosphate buffer of pH 6.0. The MTX-HSA and 5-FU-AA-HSA conjugates were very stable in rat plasma.

Effects of Endotoxin Derived from Escherichia coli Lipopolysaccharide on the Pharmacokinetics of Drugs

Yang, Kyung-Hee,Lee, Myung-Gull 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.9

Lipopolysaccharide (LPS) endotoxin is an active component in the outer membrane of Gram-negative bacteria. LPS is usually used as an animal model of chronic inflammation such as sepsis. During inflammation, development of diarrhea, and changes in the plasma protein bindings, in the hepatic and/or intestinal microsomal cytochrome P450 (CYP) isozymes, and in the renal excretion of drugs have been reported. Thus, in rats pretreated with lipopolysaccharide endotoxin isolated from Escherichia Coli (ECLPS rats), the absorption, the distribution, the metabolism, and the excretion of drugs could be expected to alter. Interestingly, in ECLPS rats, the time-dependent effects on the hepatic CYP isozymes have been reported. Thus, in ECLPS rats, the pharmacokinetics of drugs which are mainly metabolized via hepatic CYP isozymes could be expected to be time-dependent. In this review, an attempt to explain changes in the pharmacokinetics of drugs reported in the literature was made in terms of hepatic CYP isozyme changes or urinary excretion changes in ECLPS rats.

Effects of Ieucovorin on the pharmacokinetics of methotrexate in rabbits

Chang, Hong Won,Lee, Myung Gull,Lee, Hee joo,Park, Man Ki,Kim, Chong Kook 德成女子大學校 藥學硏究所 1992 藥學論文誌 Vol.3 No.1

The effects of leucovorin on the pharmacokinetics of methotrexate(MTX) were studied in rabbits. The renal tubular secretion of MTX appeared to be inhibited by administration of leucovorin, however, the efflux of MTX from the cell and/or re-entry of MTX into the cell did not seem to be affected by administrationof leucovorin.

Effects of Lipopolysaccharide Endotoxin on Pharmacokinetics of Drugs

Kyung Hee Yang,Myung Gull Lee 한국독성학회 2007 Toxicological Research Vol.23 No.4

Effects of Lipopolysaccharide on Pharmacokinetics of Drugs

Yang, Kyung-Hee,Lee, Myung-Gull Korean Society of ToxicologyKorea Environmental Mu 2007 Toxicological Research Vol.23 No.4

Lipopolysaccharide (LPS) endotoxin is an active component in the outer membrane of Gram-negative bacteria. LPS is usually used as an inflammatory animal model. During the inflammation, diarrhea and changes in plasma proteins, in hepatic and/or intestinal microsomal cytochrome P450 (CYP) isozymes, and in the renal and/or biliary excretion of drugs have been reported. Thus, in rats pretreated with lipopolysaccharide endotoxin isolated from Klebsiella pneumoniae (KPLPS rats), the absorption, distribution, metabolism, and excretion of drugs could be expected to be altered. Interestingly time-dependent effects on the hepatic CYP isozymes have been reported in KPLPS rats. Thus, in KPLPS rats, the pharmacokinetics of drugs which are mainly metabolized via CYP isozymes could be expected to be time-dependent. In this review, an attempt to explain changes in pharmacokinetics of drug reported in the literature was made in terms of CYP isozyme changes or urinary and/or biliary excretion changes in KPLPS rats.