• Biomolecules & Therapeutics
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• 제30권6호
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• pp.510-519
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• 2022

Tofacitinib, a Janus kinase 1 and 3 inhibitor, is mainly metabolized by CYP3A1/2 and CYP2C11 in the liver. The drug has been approved for the chronic treatment of severe ulcerative colitis, a chronic inflammatory bowel disease. This study investigated the pharmacokinetics of tofacitinib in rats with dextran sulfate sodium (DSS)-induced ulcerative colitis. After 1-min of intravenous infusion of tofacitinib (10 mg/kg), the area under the plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib significantly increased by 92.3%. The time-averaged total body clearance decreased significantly by 47.7% in DSS rats compared with control rats. After the oral administration of tofacitinib (20 mg/kg), the AUC increased by 85.5% in DSS rats. These results could be due to decreased intrinsic clearance of the drug caused by the reduction of CYP3A1/2 and CYP2C11 in the liver and intestine of DSS rats. In conclusion, ulcerative colitis inhibited CYP3A1/2 and CYP2C11 in the liver and intestines of DSS rats and slowed the metabolism of tofacitinib, resulting in increased plasma concentrations of tofacitinib in DSS rats.

• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.273-278
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• 2011

The aim of this study was to investigate the effect of efonidipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

• YAKHAK HOEJI
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• 제37권4호
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• pp.383-388
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• 1993

Pharmacokinetics of aucubin, an irdoid glucoside, was compared in rats of experimental hepatic failure(EHF). EHF was induced by CCI$_{4}$ or D-galactosamine pretreatment. This work was designed to find out any differences in the pharmacokinetics of aucubin that may explain the different protective effect of aucubin on CCI$_{4}$- and galactosamine-induced EHF : aucubin reportedly protected CCI$_{4}$-inducing hepatotoxicity effectively, but did not for galactosamine-hepatotoxicity. EHF was induced by intraperitoneal injection Of CCI$_{4}$(0.9ml/kg) or galactosamine(250 mg/kg) to Wistar rats 24 hr before the pharmacokinetic study. The rats were fasted during the 24 hr. Aucubin was iv injected at a dose of 15 mg/kg and the plasma aucubin was assayed by HPLC. There were no significant differences in the pathophysiologies(body weight, liver weight, GTP, hematocrit, blood cell distrbution and plasma protein binding of aucubin) between the two EHF models except GOP which was significantly (p<0.05) higher in CCI$_{4}$-than in galactosamine-EHF. On the other hand, pharmacokinetics of aucubin such as total cleatance(CL$_{t}$), distribution volume at steady-state(Vd$_{ss}$), and mean residence time(MRT) differed significantly(p<0.05) between the models : for example, CL$_{t}$ was increased two fold by CCI$_{4}$, but not by galaclosamine ; Vd$_{ss}$, in galactosamine-EHF was higher than that in CCI$_{4}$-EHF ; MRT was decreased by CCI$_{4}$, but increased conversely by galactosamine. The increase of CL$_{t}$(and decrease of MRT) in rats of CCI$_{4}$-EHF was contrary to the general expectation for the hepatic failure : most of the hepatic failures have been known to decrease CL$_{t}$ of the administered drugs. Whether the difference in the pharmacokinetics is responsible for the different protective effect of aucubin against the two EHF models is of interest. However, much more studies on biliary excretion, urinary excretion, and hepatic uptake in cellular level should be preceded before any conclusions are made on the role of different pharmacokinetics on the different pharmacology of aucubin.

• The Korean Journal of Pharmacology
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• 제31권2호
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• pp.251-259
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• 1995

Pharmacokinetics and pharmacodynamics of metoprolol, a selective beta-l blocker, were examined for 360 minutes after intravenous bolus administration of metoprolol to 6 dogs. Plasma concentration and excreted amount in the urine metoprolol were measured by liquid chromatography with fluorescence detection. PR interval and heart rate were measured by ECG monitoring. Blood pressure was monitored through intraarterial catheter in femoral artery and cardiac output by thermodilution method using Swan-Ganz catheter. To analyze the effect site concentration-response relationship, plasma concentration and pharmacological effects were simultaneously fitted to a two pharmacokinetic compartment linked to pharmacodynamic model with NONLIN program. Results are as follows. 1) The plasma concentration of metoprolol after intrvenous injection decreased biexponentially. The terminal half-life estimated was $1.33{\pm}0.40$ hours and the volume of distribution at steady state (Vdss) and the total body clearance were $1.04{\pm}0.4\;L/kg,\;6.55{\pm}2.21\;L/hr$, respectively. The central compartment volume of distribution and peripheral compartment volume of distribution were $0.35{\pm}0.14L/kg\;and\;0.69{\pm}0.34L/kg$. The renal clearance and intercompartment clearance were $0.53{\pm}0.25\;L/min\;and\;0.35{\pm}0.19\;L/min$. 2) Simulated biophase concentration-response curve shows hyperbolic relationship and the estimated concentration-effect relationship was best explained by Emax model when the prolongation of PR interval and the reduction of the heart rate were used as pharmacodynamic parameters. Emax and EC50 were estimated to be $26.3{\pm}4.7\;msec\;and\;88.8{\pm}82.3\;g/ml$ for PR interval, and $48.7{\pm}18.8\;beats/min\;and\;113.5{\pm}78.7\;ng/ml$ for heart rate, respectively. 3) The changes of cardiac output-effect site concentration relationship was best fitted by a linear model and the slope of the relationship was $0.005{\pm}0.003$. Diastolic blood pressure-effect site concentration relationship was also explained by the linear model and the slope of the relationship was $0.038{\pm}0.034$.

• Korean Journal of Applied Biomechanics
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• 제14권3호
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• pp.119-134
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• 2004

The purpose of this study was to analyze the angular momentum characteristics of the Fosbury Flop high jump and the role of the body segments for the production of 3 angular momentum components. The subjects were three male jumpers who were former Korean national team players. Their jumping motions were analyzed using the DLT method of three-dimensional cinematography. The conclusions were as follows. 1. All the forward angular momentum needed to clear the bar was created in the take-off phase. Take-off leg was the great contributor of the forward angular momentum. On the other hand, free leg produced large opposite angular momentum. 2. All subject had some lateral angular momentum before the take-off phase. Head and free leg had major contribution to the lateral angular momentum production. Take-off leg produced opposite angular momentum. 3. All subject had some twisting angular momentum, which make the back of the athlete him to the bar, before the take-off phase. Free leg was the major contributor of the twisting angular momentum. Head and trunk was the second contributor of the twisting angular momentum. 4. Total angular momentum needed to clear the bar had no significant correlation to the jumping height. 5. Subject who made excessive angular momentum showed different pattern of angular momentum production and had a poor record compared to other subject.

• Transactions of the Korean Society of Mechanical Engineers B
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• 제27권12호
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• pp.1655-1666
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• 2003

It is experimentally well-known that high anisotropies of the turbulent flow field are dominant inside the tip leakage vortex, which is attributable to a substantial proportion of the total loss and constitutes one of the dominant mechanisms of the noise generation. This anisotropic nature of turbulence invalidates the use of the conventional isotropic eddy viscosity turbulence models based on the Boussinesq assumption. In this study, to check whether an anisotropic turbulence model is superior to the isotropic ones or not, the results obtained from the steady-state Reynolds averaged Navier-Stokes simulations based on the RNG k-$\varepsilon$ model and the Reynolds stress model (RSM) are compared with experimental data for two test cases: a linear compressor cascade and a forward-swept axial-flow fan. Through this comparative study of turbulence models, it is clearly shown that the RSM, which can express the production term and body-force term induced by system rotation without introducing any modeling, should be used to predict quantitatively the complex tip leakage flow, especially in the rotating environment.

• Journal of Nutrition and Health
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• 제29권5호
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• pp.461-471
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• 1996

This study was performed to investigate the effect of dietary protein and cysteine levels on cadmium toxicity in rats. Seventy-two male rats of Sprague-Dawley strain weighting 171$\pm$3g were blocked into 12 groups according to body weight, and were raised for 30 days. cadmium chloride was given at levels of 0 or 400ppm, protein at levels of 7, 15 and 40%, and cysteine was added(total dietary cysteine contents : 0.45%) to diet or not. The results are summarized as follow. Food intake, weight gain, food were lower than those of cadmium free group. But, these were increased with increasing dietary protein level and cysteine addition. Fecal cadmium excretion was remarkably increased in high protein (40%) groups. Thus, cadmium retention rates were decreased in high protein groups. Metallothionein concentrations in liver and kidney were increased in cysteine addition, and cadmium administration. Especially, these were remarkably increased in cadmium and cysteine added groups. Urinary calcium excretion was increased with cadmium administration, but urinary protein excretion and creatinine clearance were not changed in these animal. In conclusion, food intake, weight gain and organ weights were decreased with administration. Cadmium toxicity was alleviated by increasing fecal cadmium excretion, while cysteine addition increased metallothionein concentrations in liver and kidney. From these results, it was shown that cadmium toxicity was alliviated by synergistic effect of high protein level and cysteine addition.

• Journal of Applied Biological Chemistry
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• 제58권4호
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• pp.363-368
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• 2015

The pharmacokinetics of florfenicol were studied in healthy and vibriosis-infected large yellow croaker (Pseudosciaena crocea) following administration of a single oral dose of $20mg{\cdot}kg^{-1}$ at $25{\pm}2^{\circ}C$. After oral administration, florfenicol levels in tissues (liver, kidney, muscle, serum, and skin) were analyzed using high-performance liquid chromatography. A two-compartment open model was used to describe the pharmacokinetics of florfenicol following oral administration. Compared to the healthy group, the absorption rate of vibriosis-infected fish significantly decreased, peak-time ($T_{max}$) delayed, maximum concentration ($C_{max}$) declined, total body clearance decreased, the elimination half-life ($T_{1/2{\beta}}$) was extended, and the area under the curve increased. These results indicate that a $20mg{\cdot}kg^{-1}$ oral dose of florfenicol administered once daily continuously for 4 or 5 days can be used for the treatment of Vibrio alginolyticus infection in large yellow croaker (Pseudosciaena crocea).

• Journal of Pharmaceutical Investigation
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• 제38권3호
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• pp.151-155
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• 2008

Circadian variations of acebutolol and its main metabolite, diacetolol pharmacokinetics were studied after a single oral administration of acebutolol (10 mg/kg) to eight rabbits at 10 : 00 AM (in the morning) and 10 : 00 PM (at night). The plasma concentration profiles of acebutolol were significantly different (P<0.05) between 10 : 00 AM and 22 : 00 PM, suggesting circadian variations of pharmacokinetic behaviors. A significant circadian rhythm of pharmacokinetic parameters was noted in rabbits, showing higher total body clearance (CL/F), and lower the area under the plasma concentration-time curves (AUC) of acebutolol than that at night. The half-life ($t_{1/2}$) of acebutolol and diacetolol were also significantly shorter in the morning than at night (P<0.05). Metabolite-parent AUC ratio at night significantly decreased compared to in the morning, implying that night time could inhibit acebutolol metabolism than in the morning. From this study there was an administration-time difference of acebutolol pharmacokinetics in the rabbits. The optimized dosing regimen of acebutolol can be decided by considering circadian rhythm so that the effective therapies are established for patients.

• YAKHAK HOEJI
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• 제44권6호
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• pp.539-544
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• 2000

Many diabetic patients develop serious complications during the course of the disease, including cardiovascalar disorders, nepropathy, neuropathy and retinopathy. Because some physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of drugs used to treat the disease, the pharmacokinetics of gentamycin was investigated after intravenous administration (2 mg/kg) to control rabbits and acute or chronic alloxan-induced diabetes mellitus rabbits (AIDRs). After intravenous administration, the serum concentrations of gentamycin were significantly higher between 6 and 12 hr in chronic AIDRs compared with those in control rabbits. The AUC was significant greater in chronic ($31.91\;{\pm}\;3.76\;{\mu}g/ml{\cdot}hr$) AIDRs than that in control ($21.60\;{\pm}\;2.45\;{\mu}g/ml{\cdot}hr$) rabbits. Total body clearance (CLt) in AIDRs were significantly decreased compared with that in control rabbits. Cumulative urinary excretion of gentamycin was decreased, although not significantly, in AIDRs compared with that in control rabbits.