• YAKHAK HOEJI
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• v.46 no.4
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• pp.265-269
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• 2002

The purpose of this study was to report the pharmacokinetic changes of cyclosporine after oral administration of cyclosporine, 10 mg/kg, in rabbits coadministered or pretreated twice per day for 3 days with nimodipine, dose of 5 mg/kg. The area under the plasma concentration-time curve (AUC) of cyclosporine was significantly higher in rabbits pretreated with nimodipine than that in control rabbits (p＜0.01), showing about 149％ increased relative bioavailability. The peak plasma concentration (C$_{max}$), elimination half-life (t$_{1}$2/) and MRT of cyclosporine were increased significantly (p＜0.05) in rabbits pretreated with nimodipine compared with those in control rabbits. This findings could be due to significant reduction of elimination rate constant and total body clearance by pretreated with nimodipine. The effects of nimodipine on the pharmacokinetics of oral cyclosporine were more considerable in rabbits pretreated with nimodipine compared with those in control rabbits. The results suggest that the dosage of cyclosporine should be adjusted when the drug would be coadministered chronically with nimodipine in a clinical situation.n.

• YAKHAK HOEJI
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• v.54 no.4
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• pp.252-257
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• 2010

The aim of this study was to investigate the effect of resveratrol on the pharmacokinetics of nifedipine in rats. The pharmacokinetic parameters of nifedipine were measured after the oral administration of nifenipine (6 mg/kg) in the presence or absence of resveratrol (0.5, 2.5 and 10 mg/kg, respectively). The effect of resveratrol on the P-glycoprotein (Pgp), CYP 3A4 activity was also evaluated. Resveratrol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 0.94 ${\mu}M$. In addition, resveratrol significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared to the control groups, the presence of 2.5 mg/kg and 10 mg/kg of resveratrol significantly (p<0.05, p<0.01) increased the area under the plasma concentrationtime curve (AUC) of nifedipine by 49~75%, and the peak concentration ($C_{max}$) of nifedipine by 48~66%. The absolute bioavailability (AB%) of nifedipine was significantly (p<0.05) increased by 22.9-34.8% compared to the control (19.8%). The terminal half-life ($T_{1/2}$) of nifedipine was significantly (p<0.05) increased compared to the control. While there was no significant change in the time to reach the peak plasma concentration ($T_{max}$) of nifedipine in the presence of resveratrol. It might be suggested that resveratrol altered disposition of nifedipine by inhibition of both the CYP3A and P-glycoprotein efflux pump in the small intestine of rats. In conclusion, the presence of resveratrol significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of resveratrol or resveratrol-containing dietary supplenment with nifedipine should require close monitoring for potential drug interation.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.255-260
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• 2011

The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 $mg{\cdot}kg^{-1}$) with ticlopidine (3 or 9 $mg{\cdot}kg^{-1}$). The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activities were also evaluated. Ticlopidine inhibited CYP3A4 enzyme activity in a concentrationdependent manner with a 50% inhibition concentration ($IC_{50}$) of 35 ${\mu}M$. In addition, ticlopidine did not significantly enhance the cellular accumulation of rhodamine-123 in NCI/ADR-RES cells overexpressing P-gp. Compared with the control (given diltiazem alone), ticlopidine significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration ($C_{max}$) and the area under the plasma concentration-time curve (AUC) of diltiazem were significantly (9 $mg{\cdot}kg^{-1}$, p<0.05) increased in the presence of ticlopidine. The AUC of diltiazem was increased by 1.44-fold in rats in the presence of ticlopidine (9 $mg{\cdot}kg^{-1}$). Consequently, the absolute bioavailability (A.B.) of diltiazem in the presence of ticlopidine (9.3-11.5%) was signifi cantly higher (9 $mg{\cdot}kg^{-1}$, p<0.05) than that in the control group (8.0%). Although ticlopidine significantly (p<0.05) increased the AUC of desacetyldiltiazem, the metabolite-parent AUC ratio (M.R.) in the presence of ticlopidine (9 $mg{\cdot}kg^{-1}$) was significantly decreased compared to that in the control group, implying that ticlopidine could effectively inhibit the metabolism of diltiazem. In conclusion, the concomitant use of ticlopidine significantly enhanced the oral bioavailability of diltiazem in rats by inhibiting CYP3A4-mediated metabolism in the intestine and/or liver rather than by inhibiting intestinal P-gp activity or renal elimination of diltiazem.

• Archives of Pharmacal Research
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• v.24 no.3
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• pp.219-223
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• 2001

Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving$^{14}C$-procyclidme in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., $60{\mu}$l/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to doss at a dose of 0.3 mg/kg(i.e., $6{mu}$l/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of Procyclidine in rats and dogs, based on the radioactivity was calculated to be 81.1 and 98.6% respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.

• Journal of Pharmaceutical Investigation
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• v.37 no.6
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• pp.339-347
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• 2007

SMEDDS is mixture of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal(GI) tract. The main purpose of this work is to prepare self-microemulsifying drug delivery system(SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, atorvastatin calcium. Solubility of atorvastatin calcium was determined in various vehicles. Pseudo-ternary phase diagrams were constructed to identity the efficient self-emulsification region and particle size distributions of the resultant micro emulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were $Capryol^{(R)}$ 90(50%), Tetraglycol(16%), and $Cremophor^{(R)}$ EL(32%). The release rate of atorvastatin from SMEDDS was significantly higher than the conventional tablet ($Lipitor^{(R)}$), 2-fold. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as atorvastatin calcium by the oral route.

• Mass Spectrometry Letters
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• v.12 no.4
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• pp.200-205
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• 2021

Polynemoraline C, a pyridocoumarin alkaloid, exhibits anticholinergic, anti-inflammatory, antitumor, and antimicrobial activities. A sensitive analytical method of polynemoraline C in mouse plasma was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Polynemoraline C and ¹³C-caffeine (internal standard) in mouse plasma were extracted using a liquid-liquid extraction method coupled with ethyl acetate. This extraction method resulted in high and reproducible extraction recovery in the range of 73.49%-77.31% with no interfering peaks around the peak retention time of polynemoraline C and ¹³C-caffeine. The standard calibration curves for polynemoraline C were linear over the range of 0.5-200 ng/mL with r² > 0.985. The accuracy, precision, and the stability of the data were within acceptable limits on the FDA guideline. After intravenous and oral administration of polynemoraline C at doses of 5 and 30 mg/kg, respectively, the present method was successfully applied to the pharmacokinetic study of polynemoraline C. Polynemoraline C in mouse plasma showed a multi-exponential elimination pattern with a high volume of distribution values. This compound's absolute oral bioavailability was found to be 17.0%. Polynemoraline C's newly developed LC-MS/MS method can be used for further studies on the efficacy, toxicity, and biopharmaceutics of polynemoraline C, as well as its pharmacokinetic studies.

• YAKHAK HOEJI
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• v.50 no.5
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• pp.301-307
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• 2006

A simple and sensitive high-performance liquid chromatographic method for quantitation of hydrochlorothiazide in human plasma was developed and bioavailability parameters of hydrochlorothiazide were assessed in Korean healthy male volunteers. Caffeine was used as an internal standard. Hydrochlorothiazide and internal standard in plasma sample were extracted using tert-butylmethylether (TBME). A centrifuged upper layer was then evaporated and reconstituted with mobile phase of acetonitrile-25 mM phosphate buffer (20/80, pH 2.5). The reconstituted samples were injected into a Luna C18 column $(250{\times}4.6\;mm,\;5{\mu}m)$ at a flow-rate of 1.0 ml/min. The wavelength was set at 230 nm and no endogenous substances were found to interfere, A linear relationship for hydrochlorothiazide was found in the range of $10{\sim}300\;ng/ml$. The lower limit of quantitation (LLOQ) was 10 ng/ml with acceptable precision and accuracy. Assayed in plasma, the intra- and inter-day validation for all coefficients of variation (R.S.D.%) were found less than 15%. Main pharmacokinetic parameters of 50mg of hydrochlorothiazide were revealed as follows: $AUC_t\;1761{\pm}509.0\;ng{\cdot} hr\;ml,\;C_{max}\;296.5{\pm}95.5\;ng/ml,\;T_{max}\;1.94{\pm}0.85hr,\;K_{el}\;0.12{\pm}0.04\;hr^{-1}\;and T_{12}\;6.81{\pm}2.92\;hr.\;C_{max}\;and\;T_{max}$ were in accordance with the values $(270{\sim}350\;ng/ml\;and\;1.9{\sim}2.7\;hr)$ of Caucasian.

• Journal of Pharmaceutical Investigation
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• v.34 no.6
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• pp.513-519
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• 2004

A sensitive method for quantification of pinaverium bromide in human plasma was established using liquid chromatography-electrospray ionization tandem mass spectrometry(LC-ESI-MS/MS). Glimepiride was used as internal standard. Pinaverium bromide and internal standard in plasma sample were extracted using tert-butylmethylether(TBME). A centrifuged upper layer was then evaporated and reconstituted with mobile phase of acetonitrile-5 mM ammonium formate (80/20, pH 3.0). The reconstituted samples were injected into a $C_{18}$ reversed-phase column. Using MS/MS with multiple reaction monitoring (MRM) mode, pinaverium and glimepirde were detected without severe interference from human plasma matrix. Pinaverium produced a protonated precursor ion $([M+H]^+)$ at m/z 510.3 and a corresponding product ion at m/z 228.9. Internal standard produced a protonated precursor ion $([M+H]^+)$ at m/z 491.5 and a corresponding product ion at m/z 352.0. Detection of pinaverium bromide in human plasma was accurate and precise, with limit of quantitation at 0.5 ng/ml. The method has been successfully applied to bioavailability study of pinaverium bromide tablet in Korean healthy male volunteers. Pharmacokinetic parameters such as $AUC_t,\;C_{max},\;T_{max},\;K_{el}\;and\;t_{1/2}$ were calculated.

• Archives of Pharmacal Research
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• v.22 no.3
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• pp.288-293
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• 1999

Postabsorptive serum iron level was determined after oral administration of the compounds to human. In serum and whole blood, $Fe^{3+}$ was measured by ion chromatography (IC) using a pyridine-2,6-dicarboxylic acid (PDCA) as an eluent. The serum sample solutions were pretreated with I N HCI and 50% TCA. The whole blood sample solutions were treated with 3 N HCI for 30 min at $125^{\circ}C$. The limit of detection (LOD) of the IC technique is $0.2 {\mu}M$ for$Fe^{2+}$and 0.1 $\mu$M for $Fe^{3+}$. The area under concentration (AUC) can be obtained by the above analytical condition. In addition, to compare the stability of $Fe^{2+}$ to that of $Fe^{3+}$ in pharamaceutical preparations, accelerated stability test was carried out. After storing the samples under $40^{\circ}C$, 75%RH in light-resistant container for various time intervals, the contents of iron of different valencies were determined separately by the IC technique and the change and/or the interchange of among those iron species in preparations was investigated. Iron raw materials are stable, but $Fe^{2+}$ in$Fe^{3+}$ source materials was slightly converted to $Fe^{3+}$ by oxidation. $Fe^{2+}$ in$Fe^{3+}$ source raw materials and $Fe^{3+}$ in $Fe^{2+}$ raw materials are determined as impurities. Therefore, IC technique is found to be an appropriate method for comparative evaluation of dissimilar bioavailability of $Fe^{2+}$ and $Fe^{3+}$, stability of $Fe^{2+}$ and $Fe^{3+}$ raw materials and preparations.

• Nutrition Research and Practice
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• v.15 no.5
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• pp.541-554
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• 2021

BACKGROUND/OBJECTIVES: Isoflavones (ISFs) are effective in preventing bone loss, but not effective enough to prevent osteoporosis. Mixtures of soy ISF and lecithin (LCT) were prepared and characterized in an attempt to improve the bone loss. MATERIALS/METHODS: The daidzein (DZ) and genistein (GN) solubility in soy ISF were measured using liquid chromatography-mass spectrometry. The change in the crystalline characteristics of soy ISF in LCT was evaluated using X-ray diffraction analysis. Pharmacokinetic studies were conducted to evaluate and compare ISF bioavailability. Animal studies with ovariectomized (OVX) mice were carried out to estimate the effects on bone loss. The Student's t-test was used to evaluate statistical significance. RESULTS: The solubility of DZ and GN in LCT was 125.6 and 9.7 mg/L, respectively, which were approximately 25 and 7 times higher, respectively, than those in water. The bioavailability determined by the area under the curve of DZ for the oral administration (400 mg/kg) of soy ISF alone and the soy ISF-LCT mixture was 13.19 and 16.09 ㎍·h/mL, respectively. The bone mineral density of OVX mice given soy ISF-LCT mixtures at ISF doses of 60 and 100 mg/kg daily was 0.189 ± 0.020 and 0.194 ± 0.010 g/mm³, respectively, whereas that of mice given 100 mg/kg soy ISF was 0.172 ± 0.028 g/mm³. The number of osteoclasts per bone perimeter was reduced by the simultaneous administration of soy ISF and LCT. CONCLUSIONS: The effect of preventing bone loss and osteoclast formation by ingesting soy ISF and LCT at the same time was superior to soy ISF alone as the bioavailability of ISF may have been improved by the emulsification and solvation of LCT. These results suggest the possibility of using the combination of soy ISF and LCT to prevent osteoporosis.