• Archives of Pharmacal Research
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• v.13 no.2
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• pp.147-150
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• 1990

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.

• Korean Journal of Clinical Pharmacy
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• v.1 no.1
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• pp.31-36
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• 1991

Tobramycin is one of the most frequently selected agents for pharmacokinetic drug monitoring because of its narrow therapeutic index and essential role for the management of serious infections, especially gram-negative infections. Its pharmacokinetic parameters are dependent on race, sex, age, ideal body weight. disease states, and etc. Therefore, to schedule the dosing of tobramycin, the individual pharmacokinetic parameters such as half-life and volume of distribution are needed. However, these pharmacokinetic parameters have never been reported in Koreans. The purposes of this study were to evaluate the volume of distribution of tobramycin in cancer patients who had normal renal function, to compare the mean values of Vd reported in the literature, and to compare the measured half-life with the expected half-life based on ABW, LBW, and IBW, respectively. Venous blood samples were collected just before and thirty minutes after dosing during steady state. Serum tobramycin concentrations were determined by $TD_x$ (fluorescence immunoassay). IBW were measured by the method of Devine: and LBW were measured by the method of Hallynck. Creatinine clearances (CLcr) of the patients were estimated using the Cockcroft and Gault equation. Elimination rate constants (kel) were determined using the Welling and Craig equation. Infusion rate (ko), volume of distribution (Vd), and half-life $(t_{1/2})$ were determined using the Saw chuk and Zaske equation. The volume of distribution Was $27\%$ greater than the Schentag's study (0.26 vs 0.33 l/kg), but the half-life was similar to the Levy's study. The predicted half-lives based on IBW were the closest to actual half-lives (1.85 vs 2.01 hr).

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.7 no.2
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• pp.99-103
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• 2021

In this study, the initial in vivo pharmacokinetic changes according to the routes of drug administration were investigated using bioimaging techniques. The purpose of this study was to quantify the degree of distribution of each major organ in normal mice over time by acquiring Positron Emission Tomography/Computed Tomography images while administering routes F-18 fluorodeoxyglucose such as intravenous, intraperitoneal and per oral, a representative diagnostic radiopharmaceutical. Dynamic Positron Emission Tomography images were acquired for 90 minutes after drug administration. Radioactivity uptake was calculated for major organs using the PMOD program. In the case of intravenous administration, it was confirmed that it spread quickly and evenly to major organs. Compared to intravenous administration, intraperitoneal administration was about three times more absorbed and distributed in the liver and intestine, and it was showed that the amount excreted through the bladder was more than twice. In the case of oral administration, most stayed in the stomach, and it was showed that it spread slowly throughout the body. In comparison with intravenous administration, it was presented that the distribution of kidneys was more than 9 times and the distribution of bladder was 66% lower. Since there is a difference in the initial in vivo distribution and excretion of each administration method, we confirmed that the determination of the administration route is important for in vivo imaging evaluation of new drug candidates.

• Biomolecules & Therapeutics
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• v.5 no.3
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• pp.284-291
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• 1997

The pharmacokinetics and tissue distribution of DWP20367 (1-cyclopropyl-6-fluoro-8-chloro-7-(2, 7-diazabicyclo[3,3,0]tract-4-ene-7-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid), a novel fluoroquinolone, were examined in rats and beagle dogs after a single intravenous and oral administration. Analysis of DWP20367 in plasma, tissue, and urine was determined by both HPLC and microbiological assay (bioassay). The plasma concentration-time curves of the drug in rats and beagle dogs were biexponentially declined. The terminal half-life (t$_{1}$2$\beta$/) of the drug in rats was about 60.1 $\pm$7.3 min (i.v.) and 61.3 $\pm$ 12.4 min (p.o.) in bioassay, and 86.3 $\pm$19.8 min (i.v.) and 50.9$\pm$ 14.9 min (p.o.) in HPLC. In beagle dogs, half-life of the drug determined by bioassay was about 121.8$\pm$6.2 min (i.v.) and 111.0$\pm$7.6 min (p.o.). The volume of distribution at steady-state (Vd$_{ss}$ ) was 243.8$\pm$74.1 ml/kg (bioassay) and 339.2$\pm$84.3 ml/kg (HPLC) in rats, and 1587.5 $\pm$536.9 ml/kg (bioassay) in beagle dogs. The total body clearance (Cl$_{t}$) of DWP20367 was 3.4 $\pm$ 0.4 ml/min/kg (bioassay) and 2.4$\pm$0.4 ml/min/kg (HPLC) in rats, and 12.3$\pm$ 1.0 ml/min/kg (bioassay) in beagle dogs, respectively. The extent of bioavailability after oral administration was 89.1%(bioassay) and 79.9% (HPLC) in rats, and 78.7% (bioassay) in beagle dogs. Urinary recovery (24-h) assayed by bioassay was 0.7% (p.o.) and 1.2% (i.v.) in rats, and 0.8% (p.o.) and 1.0% (i.v.) in beagle dogs. In rats, 24-h fecal recovery determined by bioassay was 11.2% (p.o.) and 0.1% (i.v.). Rat and human serum protein binding ratios at 2$\mu$g/ml were about 90~91%. This drug determined by bioassay was also distributed by the order of liver, kidney, lung, heart, spleen and muscle 30 min after oral administration.on.

• YAKHAK HOEJI
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• v.40 no.5
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• pp.491-500
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• 1996

The organ distribution and pharmacokinetics of DWP401, a recombinant human epidermal growth factor (rhEGF), were compared after single and repeated subcutaneous administration ( 50${\mu}$/kg, 10${\mu}g$Ci/kg of $^{125}I$-DWP401, twice a day for 7 consecutive days) to rats. The pharmacokinetic parameters such as AUC and terminal half-life were similar between two different administration. During repeated administration, the plasma concentration of DWP401 seemed to be constant when the plasma was collected at 15 min after each dosing. The TCA-precipitated radioactivities in thyroid, liver, kidney, and stomach were higher than those of other organs studied after both single and repeated administration. The TCA-precipitated radioactivities after repeated administration in several organs, such as thyroid, stomach, prostate, adrenal, eye ball, and testis were higher than those after single administration. But, according to the observations using gel filtration chromatography and antibody binding assay, the radioactivities in thyroid and stomach were not primarily due to the intact DWP401 or its metabolites but due to the $^{125}I$-thyroxine binding protein. In conclusion, it can be suggested that DWP401 is metabolized to each amino acid or small polypeptides, and there was no significant changes in pharmacokinetics or any indications for accumulation of DWP401 in rat plasma and organs after repeated treatment.

• YAKHAK HOEJI
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• v.36 no.6
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• pp.591-597
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• 1992

The organ distribution of $[^3H]$-methotrexate-lactosaminated bovine serum albumin conjugates ($[^3H]$-MTX-LBSA) was investigated to examine their role as a liver-specific anticancer drug. Synthesis of lactosaminated bovine serum albumin(LBSA) with BSA, lactose and sodium cyanoborohydride through reductive amination was followed by its conjugation with methotrexate (MTX) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), thereby synthesizing [$[^3H]$-MTX-LBSA conjugates. Organ distribution and plasma elimination profiles were studied in male Wistar rats after intravenous injection of [$[^3H]$-MTX-LBSA conjugates. The fates of $[^3H]$-MTX and the $[^3H]$-MTX-BSA conjugates´fates were also investigated for comparison. The results showed that the plasma level of $[^3H]$-MTX-LBSA conjugates declined more rapidly than those of $[^3H]$-MTX-BSA and their liver concentration was significantly higher than those of other treatment (p<0.01). In addition, their uptake compared to the amount taken up by the liver (1 : 33.1 at 10 min, 1 : 24.1 at 120 min). All these suggested that MTX-LBSA conjugate is one of the drug delivery system (DDS) that is advanced in concentrating MTX in the liver and minimizing the renal toxicity of MTX.

• Journal of Pharmaceutical Investigation
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• v.33 no.4
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• pp.287-292
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• 2003

A novel antitumor agent, antibody-endostatin fusion protein $(anti-HER2/neu\;IgG3C_H3-Endostatin,\;AEFP)$ formed by genetic engineering procedure from antibody (Ab) which specifically targets to tumor cells ad angiogenesis inhibitor, endostatin (Endo) that has excellent antitumor effect, minimizes the toxicity of normal cells and selectively kills only tumor cells. The purpose of this study is to evaluate the phamacokinetic parameters and to analyze the localization of AEFP. After an intravenous injection of $150\;{\mu}l\;(5\;{\mu}Ci)\;[^{125}I]Ab,\;[^{125}I]AEFP$ to mice, blood was collected though retroorbital plexus from 15 min to 2880 min. Following the jugular vein injetion of $150\;{\mu}l\;(10\;{\mu}Ci)\;[^{125}I]Endo$, blood was collected by the use of carotid artery cannulation from 0.25 min to 30 min. Consequently, Endo was very rapidly removed from plasma compartment within 30 min. On the other hand, AEFP similar to Ab was slowly cleared from plasma. Also, Endo was metabolized about 40% within 30 min. However, AEFP was shown to metabolize less than 10% within 2880 min. The organ distribution of Endo was in order kidney, lung, spleen. Both Ab and AEFP were localized in order spleen, kidney, liver. Futhermore the tumor/blood distribution ratio of AEFP at 96 hours after injection is about 20 times higher than it of Endo at one hour after injection. In conclusion, these studies demonstrate that the anti-cancer or suppression of angiogenesis effect of Endo may be improved by the use of AEFP because the longer half life and stability of AEFP is able to selectively target antigens expressed on tumors.

• Korean Journal of Veterinary Research
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• v.51 no.4
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• pp.253-257
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• 2011

Amikacin is a semisynthetic derivative of kanamycin and primarily active against aerobic Gram-negative-pathogens with limited activity against Gram-positive bacteria. Meager study was reported on pharmacokinetic data on multi-days administration of amikacin. Hence, pharmacokinetics study was done in five clinically healthy goats (n = 5), after intravenous bolus injection of amikacin sulfate at the dose rate of 10 mg/kg body weight daily for three consecutive days. The amikacin concentrations in plasma and pharmacokinetics-parameters were analyzed by using microbiological assay technique and noncompartmental open-model, respectively. The mean peak plasma concentrations (Mean ${\pm}$ SD) of amikacin at time zero ($Cp^{0}$) was $114.19{\pm}20.78$ and $128.67{\pm}14.37{\mu}g/mL$, on day 1st and 3rd, respectively. The mean elimination half-life ($t_{1/2}ke$) was $1.00{\pm}0.28h$ on day 1st and $1.22{\pm}0.29h$ on day 3rd. Mean of area under concentration-time curve ($AUC_{0{\rightarrow}{\infty}}$) was $158.26{\pm}60.10$ and $159.70{\pm}22.74{\mu}g.h/mL$, on day 1st and 3rd respectively. The total body clearance ($Cl_{B}$) and volume of distribution at steady state (Vdss) on day 1st and 3rd were $Cl_{B}=0.07{\pm}0.02$ and $0.06{\pm}0.01L/h.kg$ and $Vdss=0.10{\pm}0.03$ and $0.11{\pm}0.05L/kg$, respectively. No-significant difference was noted in both drug-plasma concentration and pharmacokinetics-parameters, respectively. Amikacin concentration in plasma was found higher up-to 4 h and 6 h onward on down-ward trends favour to reduce toxicity. Which also support the pharmacokinetic-pharmacodynamic way of dosing of aminoglycosides and hence, amikacin may be administered 10 mg/kg intravenously daily to treat principally Gram-negative pathogens and limitedly Gram-positive-pathogens.

• YAKHAK HOEJI
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• v.34 no.6
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• pp.375-383
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• 1990

The pharmacokinetics of haloperidol were determined after single oral and intravenous doses in 13 male schizophrenic patients. Plasma concentrations of haloperidol(HP) and reduced haloperidol(RH) were measured by high performance liquid chromatography. Plasma concentration data obtained were analyzed by obth model dependent (one-or two exponential decay models using nonlinear regression) and model independent (AUC and first moment curve) approaches. The two methods were found to be in close results. After intravenous injections of HP in 8 patients (10 mg/man), the mean central and peripheral volume of distributions were $2.85\;{\pm}\;1.70$ and $8.09\;{\pm}\;2.10\;l/kg$, respectively, and mean steady state volume of distribution was $11.87\;{\pm}\;3.21\;l/kg$. Mean clearance, MRT and elimination half life were $12.39\;{\pm}\;3.25\;ml/min/kg$, $925.10\;{\pm}\;166.79\;min$ and $676.35\;{\pm}\;126.45\;min$, respectively. After oral administrations of HP in 5 patients, mean peak time and peak concentration were $217.63\;{\pm}\;61.60\;min$ and $9.77\;{\pm}\;2.92\;ng/ml$, respectively. Mean MRT and elimination half life were $1112.23\;{\pm}\;131.73\;min$ and $724.02\;{\pm}\;120.03\;min$, respectively, and these parameters were not significantly different from those of intravenous injection of HP. Absolute bioavailability of HP oral product was found to be about 44%. The profiles of plasma RH concentration-time curves after oral or intravenous doses of HP were similar. Also it was found that the elimination rate of RH was solwer than that of HP by comparing the slopes of plasma concentration-time curves of HP and RH.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.2
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• pp.99-104
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• 2015

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra- abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, $C_{max}$ was $11.151{\mu}g/mL$ at 5 min after the intravenous injection and $t_{1/2}$ was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.