• Toxicological Research
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• 제18권4호
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• pp.311-324
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• 2002

Toxicokinetic studies are intended to provide critical evaluation of drug disposition at toxico-logical doses and help understand the relationship between blood or tissue levels and the time course of toxic events. Relatively high dose levels wed in toxicokinetics, compared to pharmacokinetics, complicates absorption, protein binding, metabolism and elimination processes. In this mini review, frequently wed toxicokinetic models such as linear compartment models, physiological models, and nonlinear kinetic mod-ec are introduced. In addition, optimization of toxicokinetic studies, their role in the drug development process, and prediction oj human toxicokinetics based on animal data by interspecies scaling are briefly discussed.

• Journal of Pharmaceutical Investigation
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• 제12권4호
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• pp.153-174
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• 1982

• Journal of Pharmaceutical Investigation
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• 제13권2호
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• pp.51-58
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• 1983

In order to elucidate the effects of Panax Ginseng on the pharmacokinetic parameters of nalidixic acid in a patho-physiological changes, the kinetics of the disappearance of the drug from the blood, appearance in the bile and urinary excretion were studied in $CCl_4-toxicated$ rabbits. The pharmacokinetics of the drug nalidixic acid in rabbits were modeled by a two compartment. Total saponin, water extract from Panax Ginseng, significantly decreased biliary and urinary excretion of nalidixic acid.

• Archives of Pharmacal Research
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• 제26권6호
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• pp.499-503
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• 2003

Because physiological changes that potentially alter pharmacokinetics occurs in diabetes mellitus patients, pharamacokinetics of drugs used in the treatment of hypertension was studied using acebutolol as a model anti-hypertensive drug. Thus, the pharmacokinetics of acebutolol was investigated after oral administration of acebutolol (15 mg/kg) to control rabbits and rabbits with acute or chronic diabetes mellitus induced by alloxan. Kidney and liver functions were documented for acute and chronic diabetes mellitus groups based on plasma chemistry data. After oral administration of acebutolol to acute and chronic groups, the plasma concentrations appeared higher; As a result, area under the plasma concentration-time curve from time zero to time infinity10575 and 8668 $\mu g\cdot$ h/mL for acute and chronic group, respectively. In comparison, the area was apparently smaller in the control group (i.e., 7132 $\mu g\cdot$ h/mL). The half-life in acute groups was significantly prolonged 8.45 h compared with the half-life in the control group (i.e., 6.30 h). Alteration in acebutolol pharmacokinetics was more pronounced in the acute group as evidenced by the significantly higher values the area under the plasma concentration time curve, absorption rate constant and maximum plasma concentration compared with chronic or control group. Therefore, these observations indicate that acebutolol pharmacokinetics may be affected in patients with diabetes mellitus, especially in the early stage of the disease.

• Archives of Pharmacal Research
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• 제10권4호
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• pp.250-257
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• 1987

The development of physiologically based pharmacokinetic model for drug distribution and excretion is described. The physiological modeling procedure is useful in animal and clinical applications to obtain fundamental knowledge of the transport and metabolism of a substance in vivo. In this paper a review of physiologically based pharmacokinetics is presented in the hope of understanding and increasing the use of this modelling technique. The method of model development and the composition of equations based on the different models are explained. For the better understanding a physiological pharmacokinetic model of tenoxicam disposition in the rat is presented as an example of flow limited model.

• Archives of Pharmacal Research
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• 제25권5호
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• pp.709-717
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• 2002

Hypoxemia is known to induce various physiological changes which can result in alteration in drug pharmacokinetics. To examine the effect of acute moderate hypoxemia on metoclopramide (MCP) pharmacokinetics, a continuous 14-hour infusion of MCP during a normoxemic, hypoxemic and subsequent normoxemic period was conducted in eight adult sheep. Arterial blood and urine samples were collected to examine the effects on the pharmacokinetics of MCP and its deethylated metabolites. MCP and its mono- and di-deethylated metabolites were quantitated using a GC/MS method. Steady-state concentrations of MCP were achieved in each of the three periods. During hypoxemia, MCP plasma steady-state concentration increased significantly from 50.72$\pm$1.06 to 63.62$\pm$1.79 ng/mL, and later decreased to 55.83$\pm$1.15 ng/mL during the post-hypoxemic recovery period. Total body clearance ($CL_{TB}$) of MCP was significantly decreased from 274.2$\pm$48.0 L/h to 205.40$\pm$28.2 L/h during hypoxemia, and later restored to 245.8$\pm$44.2 L/h during the post-hypoxemic period. Plasma mono-deethylated MCP concentration (32.78$\pm$1.73 ng/mL) also increased, compared to the control group (21.20$\\pm$1.39 ng/mL), during hypoxemia and subsequent normoxemic period. Renal excretion of MCP and its metabolites was also decreased during hypoxemia, while urine flow was increased with a concomitant decrease in urine osmolality. Thus, the results indicate that acute moderate hypoxemia affects MCP pharmacokinetics.

• 약학회지
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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.

• Archives of Pharmacal Research
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• 제20권1호
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• pp.24-28
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• 1997

In the present study, a pharmacokinetic model to address the effects of the diffusional barrier between splanchnic bed and enterocytes on the extent of presystemic and systemic intestinal elimination of drugs was developed. The model is composed of five compartments, ie., gut lumen, enterocyte, splanchnic bed, liver and central compartments. The equations for various pharmacokinetic parameters important for estimating the quantitative differences between presystemic and systemic intestinal and hepatic elimination of drugs were derived. A simulation study demonstrated that the diffusions[ barrier present between splanchnic blood and enterocytes can have significant effects on oral bioavailability and systemic clearance of drugs. In conclusion, the model can be useful for a better understanding of the effects of diffusional barrier on the extent of administration-route dependent intestinal and hepatic elimination of drugs, especially those with high hydrophilicity and/or charge(s) under physiological conditions.

• 동의생리병리학회지
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• 제34권4호
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• pp.201-208
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• 2020

The effects of Gamisoyo-san (GMSYS) co-administration within 5 min on the pharmacokinetics (PK) of tamoxifen were observed. After 50 mg/kg of tamoxifen oral treatment, GMSYS 100 mg/kg was orally administered within 5 min to 7-wk old male SPF.VAF Outbred Crl:CD [Sprague-Dawley (SD)] rats. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of GMSYS treatment, and plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. Tmax, Cmax, AUC, t1/2 and MRTinf of tamoxifen were analysis as compared with tamoxifen single administered rats. Although co-administration with GMSYS did not critically influenced on the pharmacokinetic parameters of oral tamoxifen, they induced increased trends of plasma tamoxifen concentrations, especially significant (p<0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5 hr after end of co-administration with GMSYS as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 10 mg/kg and GMSYS 100 mg/kg within 5 min. It is considered that pharmacokinetic studies should be tested like the effects of GMSYS on the pharmacokinetics of tamoxifen, when they were co-administered with prolonger intervals than Tmax of tamoxifen oral administration (about 2.5 hr-intervals), to achieve the optimal dosing regimen of GMSYS and tamoxifen co-administration.

• Toxicological Research
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• 제18권3호
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• pp.215-226
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• 2002

Acute or repeated physical exercise affects a large number of physiological parameters including hemodynamics, respiration, pH, temperature, gastrointestinal function and biotransformation, which determine the pharmacokinetics of drugs and chemicals. The rate and the amount of a chemical reaching the active site are altered by physical exercise, which results in significant changes in pharmacolosical/toxicological activity of the chemical. This aspect of physical exercise has vast implication in therapeutics and in safety evaluation, particularly for chemicals that have a low margin of safety. However there appears to be a wide inter- and intraindividual variation in the effects of physical exercise depend-ing on the duration, intensity and type of exercise, and also on the properties of each chemical. It is suggested that more studies need to be done to determine which factor(s) plays a major role in the disposition of chemicals in human/animals performing physical exercise. Certain chemicals induce severe toxicity due to metabolic conversion to reactive intermediate metabolites. it is suggested that repeated exercise may enhance the free radical scavenging system by increasing the activity of antioxidant enzymes. This area of research remain to be explored to elucidate the interaction of exercise and chemical on the antioxidant system.