• Biomolecules & Therapeutics
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• v.5 no.1
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• pp.82-86
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• 1997

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 0.2337g 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 metabolite(5) 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 DA-5018 was lower and the metabolism of DA-5018 was higher in rabbits than that in rats.

• The Journal of Korean Medicine
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• v.41 no.4
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• pp.1-11
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• 2020

Objectives: Objectives: The object of this study was to elucidate the possible effects on the pharmacokinetics of tamoxifen after single oral co-administration of Gamisoyo-san (GMSYS) with 2.5 hr-intervals combination therapy of tamoxifen with GMSYS. Methods: After 2.5 hr of 50 mg/kg of tamoxifen treatment, GMSYS 100 mg/kg was administered. The plasma was 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. PK parameters of tamoxifen were analysis as compared with tamoxifen single administered rats. Results: Although single co-administration with GMSYS with 2.5 hr-interval induced increased trends of plasma tamoxifen concentrations, there are no significant changes on the plasma concentrations of tamoxifen were demonstrated in tamoxifen and GMSYS 100 mg/kg co-administrated rats with 2.5 hr-intervals as compared to those of tamoxifen single 50 mg/kg treated rats, and also GMSYS co-administrated rats did not showed any significant changes on the all pharmacokinetic parameters as compared to those of tamoxifen single formula treated rats. Conclusions: According to the this study, single co-administration of GMSYS with 2.5 hr-intervals did not critically influenced on the oral bioavailability of tamoxifen, suggesting GMSYS did not critically influenced on the absorption and excretion of tamoxifen, the oral bioavailability, when they were co-administered with 2.5 hr-intervals, at the dose levels of tamoxifen 50 mg/kg and GMSYS 100 mg/kg.

• Korean Journal of Clinical Pharmacy
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• v.15 no.1
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• pp.55-60
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• 2005

The aim of this study is to investigate the effect of naringin on the pharmacokinetics of tamoxifen in rats. Tamoxifen (10 mg/kg) was administered orally 0.5 h and 3 days after oral administration of naringin (5 mg/kg). The plasma concentrations of tamoxifen were increased significantly tv naringin compared to control. Absorption rate constant ($K_a$) of tamoxifen with naringin was increased significantly compared to that of the control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations ($C_{max}$) of tamoxifen with naringin were significantly higher than those of the control. Consequently, the relative bioavailability (R.B${\%}$) of tamoxifen with naringin was 2-3-fold higher than the control, and absolute bioavailability (A.B${\%}$) of tamoxifen were significantly higher (p<0.05 with coadministration, p<0.01 with pretreatment) than those of the control. The increased bioavailability of tamoxifen in rats with naringin might be associated with the inhibition by naringin of an efflux pump P-glycoprotein and the first-pass metabolizing enzyme CYP3A4.

• YAKHAK HOEJI
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• v.51 no.3
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• pp.169-173
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• 2007

The aim of this study was to investigate the effect of morin on the pharmacokinetics of nifedipine in rats. The pharmacokinetic parameters of nifedipine were measured after the oral administration of nifedipine (5 mg/kg) in the presence or absence of morin (1.5, 7.5 and 15 mg/kg, respectively). Compared to the control groups, the presence of 7.5 mg/kg and 15 mg/kg of morin significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of nifedipine by 48.5${\sim}$68.2%, and the peak concentration (C$_{max}$,) of nifedipine by 59.9~84.2%. The absolute bioavailability(AB%) of nifedipine was significantly (p<0.05) increased by 21.5${\sim}$24.5% compared to the control (14.5%). While there was no significant change in the time to reach the peak plasma concentration (T$_{max}$) and the terminal half-life (T$_{1/2}$) of nifedipine in the presence of morin. It might be suggested that morin altered disposition of nifedipine by inhibition of both the first-pass metabolism and p-glycoprotein (P-gp) efflux pump in the small intestine of rats. In conclusion, the presence of morin significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of morin or morin-containing dietary supplement with nifedipine should require close monitoring for potential drug interaction.

• Archives of Pharmacal Research
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• v.20 no.4
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• pp.318-323
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• 1997

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethyinitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life $(t_{1/2})$ in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL $(8.67{\pm}4.85%)$ decreased about four-folds, but in DMNA $(73.00{\pm}9.85%)$ similar result war observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.86-95
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• 2020

Background: Ginsenoside Rb1 (Rb1), one of the most abundant protopanaxadiol-type ginsenosides, exerts excellent neuroprotective effects even though it has low intracephalic exposure. Purpose: The present study aimed to elucidate the apparent contradiction between the pharmacokinetics and pharmacodynamics of Rb1 by studying the mechanisms underlying neuroprotective effects of Rb1 based on regulation of microflora. Methods: A pseudo germ-free (PGF) rat model was established, and neuroprotective effects of Rb1 were compared between conventional and PGF rats. The relative abundances of common probiotics were quantified to reveal the authentic probiotics that dominate in the neuroprotection of Rb1. The expressions of the gamma-aminobutyric acid (GABA) receptors, including GABAA receptors (α2, β2, and γ2) and GABAB receptors (1b and 2), in the normal, ischemia/reperfusion (I/R), and I/R+Rb1 rat hippocampus and striatum were assessed to reveal the neuroprotective mechanism of Rb1. Results: The results showed that microbiota plays a key role in neuroprotection of Rb1. The relative abundance of Lactobacillus helveticus (Lac.H) increased 15.26 fold after pretreatment with Rb1. I/R surgery induced effects on infarct size, neurological deficit score, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were prevented by colonizing the rat gastrointestinal tract with Lac.H (1 × 10⁹ CFU) by gavage 15 d before I/R surgery. Both Rb1 and Lac.H upregulated expression of GABA receptors in I/R rats. Coadministration of a GABA_A receptor antagonist significantly attenuated neuroprotective effects of Rb1 and Lac.H. Conclusion: In sum, Rb1 exerts neuroprotective effects by regulating Lac.H and GABA receptors rather than through direct distribution to the target sites.

• Journal of Pharmaceutical Investigation
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• v.31 no.2
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• pp.89-94
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• 2001

The pharmacokinetics of recombinant human granulocyte colony stimulating factor (rhG-CSF) following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of HM1041l-lyo and HM10411-liq (lyophilized and liquid formulations of rhG-CSF, recently under development by Hanmi Pharmaceutical Company) were studied in rats, and compared with that of Filgrastim (conventional formulation of rhG-CSF on market). The plasma concentration of rhG-CSF was quantified using a specific ELISA. The pharmacokinetic parameters of rhG-CSF, after i.v., i.m. and s.c. administration of Filgrastim, HM1041l-lyo and HM1041l-liq to rats at a rhG-CSF dose of $10\;{\mu}g/kg$, were almost identical among the three formulations. No dose-dependency was observed in the pharmacokinetic parameters of rhG-CSF following i.v. administration in the dose range of $5{\sim}100\;{\mu}g/kg$. rhG-CSF, after i.v. administration of the three preparations at a dose of $10\;{\mu}g/kg$ to rats, was detected at low levels in all of the body tissues with highest tissue/plasma ratio of $0.46{\sim}0.51$ for the kidney at 30 min after the administration. The pharmacokinetics of rhG-CSF, after i.v. administration to mice at a dose of $10\;{\mu}g/kg$, were comparable among the three formulations. In conclusion, HM10411-lyo and HM10411-liq exhibited similar pharmacokinetics for rhG-CSF with Filgrastim regandless of animal species. Considering the fact that HM10411 series, contrary to Filgrastim, are proteins lacking a methionine residue, the methionine moiety in rhG-CSF molecule does not appear to influence the pharmacokinetics of the protein significantly.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.243-247
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• 2011

Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been shown to be anti-inflammatory. In the present study, a possible interaction between rutaecarpine and caffeine was investigated in male Sprague Dawley rats. Twenty four hr after the oral pretreatment with rutaecarpine at 80 mg/kg for three consecutive days, rats were treated intravenously with 10 mg/kg of caffeine. Compared with control rats, the pharmacokinetic parameters of caffeine in rutaecarpine-pretreated rats were significantly changed, possibly due to the rapid metabolism. The production of three metabolites of caffeine (i.e., paraxanthine, theobromine and theophylline) was also significantly changed in rats pretreated with rutaecarpine. The present results suggest that oral rutaecarpine would change the intravenous pharmacokinetic characteristics of caffeine.

• Toxicological Research
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• v.7 no.1
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• pp.37-46
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• 1991

To evaluate the influence of ochratoxin A on the pharmarcokinetics of gentamicin, gentamicin concentrations in the serum, renal cortex and medulla together with parameters of the renal function and histological changes were compared between ochratoxin A-treated rats (0.1 mg of ochratoxin A/kg of body weight, ip, daily for 14 days) and normal rats. Gentamicin was given with a single intramuscular injection (10mg/kg of body weight). Ochratoxin A resulted in an increase of the half-life, the area under the concentration-time curve, the apparent volume of distribution and a decrease of the total body clearance of gentamicin, and accumulated significantly (p<0.01) more gentamicin in the kidneys.

• Journal of Pharmaceutical Investigation
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• v.39 no.5
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• pp.373-379
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• 2009

This study was conducted to develop a pharmacokinetic-pharmacodynamic (PK/PD) model of a direct thrombin inhibitor, argatroban to predict the concentration-effect profiles in rats. Argatroban was i.v. injected to rats at 0. 2, 0.8 and 3.2 mg/kg doses (n = 4-5 per dose), and plasma drug levels were determined by a validated LC/MS/MS assay. The pharmacokinetics of argatroban was linear over the i.v. dose range studied. The thrombin time (TT) and the activated partial thromboplastin time (aPTT) were measured in rat plasma and they were found to linearly increase with increasing the dose. A 2-compartment pharmacokinetic model linked with an indirect response pharmacodynamic model was successfully utilized to evaluate the drug concentration-response relationship.