• Archives of Pharmacal Research
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• v.27 no.2
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• pp.254-258
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• 2004

The purpose of this study was to investigate the pharmacokinetic alteration of diltiazem and its main metabolite, deacetyldiltiazem, after oral administration of diltiazem in rabbits with or with-out cimetidine co-administration. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly elevated in rabbits pretreated with cimetidine, suggesting that the oral clearance, an index of intrinsic clearance, may be decreased by the cimetidine treatment. Consistent with the increased AUC by the treatment, peak plasma concentration ($C_{max}$) for diltiazem was also elevated. Apparent volume of distribution normalized by the bioavailability (($V_{d}$/F) of diltiazem increased sigrificantly in rabbits pretreated with cimetidine increased. Taken together with the fact that the first pass metabolism for diltiazem is the primary determinant for the oral bioavailability, these observations indicate that increases in the oral clearance and (($V_{d}$/F may be a manifestation of the decreased first pass metabolism. Consistent with the hypothesis, the AUC of deacetyldiltiazem was significantly decreased in rabbits with cimetidine treatment. Ratio of deacetyldiltiazem to total diltiazem in the plasma was significantly decreased in rabbits with cimetidine treatment. These observations suggested that the metabolism of diltiazem to deacetyldiltiazem was reduced by cimetidine treatment and that the dosage of diltiazem should be adjusted when the drug is co-administered chronically with cimetidine in a clinical setting.

• YAKHAK HOEJI
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• v.38 no.5
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• pp.483-487
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• 1994

The pharmacokinetic characteristics of an 1% flurbiprofen gel were evaluated using rats in reference to IV bolus and oral administration of the drug using rats. Following the transdermal application of the gel at the dose of 2 mg/kg as flurbiprofen, the $C_{max}$ and $T_{max}$ of the drug were $2.14\;{\mu}g/ml$ and 2 hr, respectively, whereas those after the oral administration of the drug as a suspension were $9.90\;{\mu}g/ml$ and 0.25 hr, respectively. These results indicate that, by the transdermal administration fo flubiprofen as the gel, the absorption of the drug was much slowed down and the lower $C_{max}$ compared to the oral administration may reduce the systemic side effects of the drug. The relative bioavailability of the flurbiprofen gel in reference to the oral dose was 48.5%. Tissue levels of flurbiprofen following the application of 50 mg of the 1% flurbiprofen gel onto ventral skin of rats showed that the maximum drug concentrations in the skin $(8.52\;{\mu}g/g)$ and the muscle $(2.06\;{\mu}g/g)$ occurred at 2 hrs postdose. The drug concentration in the both tissues remained relatively constant over the next 6 hrs following the peak concentration.

• Korean Journal of Clinical Pharmacy
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• v.18 no.2
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• pp.120-123
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• 2008

The purpose of this study was to investigate the effect of naringin, one of flavonoids, on the pharmacokinetics and bioavailability of nimodipine in rabbits. Pharmacokinetic parameters of nimodipine were determined in rabbits after oral administration of nimodipine (16 mg/kg) with or without naringin (1, 5 or 15 mg/kg). Nimodipine was analyzed by high performance liquid chromatography using Hypersil ODS column. Naringin significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) and the peak concentration ($C_{max}$) of nimodipine at 5 and 15 mg/kg. The absolute bioavailability (AB%) of nimodipine by prescence of naringin (5 or 15 mg/kg) increased from 32.2-36.9% (p<0.05) compared to the control (22.0%). However, presence of naringin had no significant effect on the elimination rate constant ($K_{el}$) of nimodipine. There were no apparent changes of the time of peak concentration ($T_{max}$) of nimodipine by coadministration. These results suggest that the increased bioavailability and the significant changes of these pharmacokinetic parameters of nimodipine by naringin may be attributed to the potential of narigin to inhibit cytochrome P450 (CYP) 3A4 and P-glycoprotein efflux pump in the liver and intestinal mucosa.

• Bulletin of the Korean Chemical Society
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• v.32 no.5
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• pp.1587-1592
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• 2011

The aim of the present study was to improve the solubility and bioavailability of a poorly water-soluble drug in human body, using a solid dispersion technique (hot melt extrusion). The solid dispersion was prepared by cooling the hot melt of the drug in the carrier (Vitamin E TPGS and PVP). The dissolution rate of formulation 1 from a novel formulation prepared by solid dispersion technique was equal to release of formulation 6 (40% of eprosartan mesylate is in contrast to teveten$^{(R)}$) within 60 min (Table 1). The oral bioavailability of new eprosartan mesylate tablet having vitamin E TPGS and PVP K29 was tested on rats and dogs. Of the absorption enhancer and polymer tested, vitamin E TPGS and PVP K29, resulted in the greatest increases of AUC in animals (about 2.5-fold increase in rat and dog). When eprosartan mesylate was mixed with the absorption enhancer and polymer in a ratio of 2.94:2:1, vitamin E TPGS and PVP K29 improved eprosartan mesylate bioavailability significantly compared with the conventional immediate release (IR) tablet Teveten$^{(R)}$ (formulation 7). These results show that solid dispersion using vitamin E TPGS and PVP K29 is a promising approach for developing eprosartan mesylate drug products.

• Journal of Pharmaceutical Investigation
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• v.40 no.spc
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• pp.97-102
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• 2010

A novel surface-attached solid dispersion is designed to improve the solubility and oral bioavailability of poorly water-soluble drugs without crystalline change. Accordingly, it draws increasing interest because of excellent stability and no pollution for accomplishing enhanced solubility and bioavailability, which have recently been highlighted in connection with a number of higher value-added poorly water-soluble drugs. In addition, excellent stability can be attained when the poorly water-soluble drugs are not dissolved but dispersed in water and provide no crystallinity change. This solid dispersion is given by means of attaching the dissolved carriers such as hydrophilic polymer and surfactant to the surface of dispersed drug particles followed by changing the hydrophobic drug to hydrophilic form. The aim of the present review is to outline the preparation, physicochemical property and bioavailability of novel surface-attached solid dispersion with improved solubility and bioavailability of poorly water-soluble drugs without crystalline change.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.282-282
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• 1996

The purpose of this study was to prepare the nifedipine dry elixir (NDE) and coated nifedipine dry elixir (CNDE) containing nifedipine ethanol solution for improving the dissolution rate and bioavailability of nifedipine. NDE containing nifedipine and ethanol in wall materials of dextrin was prepared using a spray-dryer and then NDE was coated with eudragit acrylic resin to make CNDE. Shape and size of the NDE and CNDE were monitored by scanning electron micrograph and laser particle size analyzer In vitro dissolution tests were performed in simulated gastric and intestinal fluid. Bioavailability of NDE and CNDE were compared with drug powder suspension and commercial soft capsule after oral administration of the preparations to rats. NDE and CNDE are spherical in shape. Cross-sectional view of dry elixirs indicates the large inter cavity containing ethanolic drug solution in shell. Geometric mean diameter of NDE and CNDE is about 6.64 and 8.70 $\mu\textrm{m}$, respectively. Drug dissolution rate within first 5 min from NDE increased dramatically irrespective of dissolution medium. However, CNDE showed a particularly retarded dissolution rate in pH 1.2 simulated gastric fluid compared with NDE. The bioavailability of nifedipine in the NDE was increased dramatically compared with drug powder suspension. CNDE reduced initial burst-out plasma peak compared with NDE. CNDE as a sustained release delivery system could reduce the initial burst-out plasma peak due to controlling the release rate of nifedipine from NDE and maintain the effective plasma level over a longer period within therapeutic window with enhanced bioavailability of nifedipine.

• Korean Journal of Clinical Pharmacy
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• v.16 no.1
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• pp.57-62
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• 2006

The purpose of this study was to investigate the effect of naringenin, one of flavonoids, on the pharmacokinetics and bioavailability of diltiazem (15 mg/kg) after oral administration of diltiazem with or without naringenin (2.0, 10 and 20 mg/kg) in rabbits. Coadministration of naringenin increased the absorption rate constant $(K_a)$, the area under the plasma concentration-time curve (AUC) and peak concentration $(C_{max})$ of diltiazem compared to the control group, but only significantly (p<0.05) by 10mg/kg of naringenin coadministration. The absolute bioavailability (AB%) of diltiazem by coadministration ranges from 7.8% to 10.3%, increased more than control (7.2%), and relative bioavailability (RB%) of diltiazem is increased from 1.08- to 1.43-fold. Coadministration caused on significant changes in the terminal half-lives $(t_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of diltiazem. On the other hand, coadministration of naringenin increased the AUC desacetyldiltiazem, significantly at the dose of 10mg/kg. But the metabolite ratio (MR) was decreased, significantly at 10mg/kg of naringenin. Based on these results, we can make a conclusion that the increased bioavailability and the significant changes of these pharmacokinetic parameters might be due to naringenin, which possess the potency to inhibit the metabolizing enzyme (CYP3A4) in the liver and intestinal mucosa, and also inhibit the P-glycoprotein efflux pump in the intestinal mucosa.

• YAKHAK HOEJI
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• v.54 no.5
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• pp.370-376
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• 2010

The aim of this study is to investigate the effect of apigenin on the pharmacokinetics of tamoxifen in rats. Tamoxifen was administered orally (10 mg/kg) or intravenously (2 mg/kg) without or with oral administration of apigenin (0.4, 2.0 or 8.0 mg/kg) to rats. The effect of apigenin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Apigenin inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The plasma concentrations of tamoxifen were increased significantly by apigenin compared to control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations ($IC_{max}$) of tamoxifen with apigenin were significantly higher than those of the control group. Consequently, the relative bioavailability (RB%) of tamoxifen with apigenin was 2-3-fold higher than the control, and absolute bioavailability (AB%) of tamoxifen were significantly higher (p<0.05 with co-administration, p<0.01 with pretreatment) than those of the control. The increased bioavailability of tamoxifen in rats with apigenin might be associated with the inhibition of an efflux pump P-glycoprotein and CYP3A4 by apigenin. From these results, dosage regimen of tamoxifen may be need to adjust when concomitantly administered with apigenin.

• Journal of Pharmaceutical Investigation
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• v.19 no.3
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• pp.131-136
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• 1989

This study was attempted to investigate the dissolution rate and the bioavailability after oral administration of commercially available aspirin tablets in normal volunteers. The dissolution test was conducted in artificial gastric juice using basket method with three aspirin preparations (A, B and C) which were chemically equivalent. The results were as follows; The dissolution rate was higher in the order of three different brand B>A >C. Area under the blood concentration and peak blood concentration were larger in the order of brand A>B>C. Absorption rate constant and peak time were larger in the order of brand B>A>C, and there was a little difference in elimination rate constant and biological half-life. The correlation of the dissolution rate and absorption rate constant, as well as correlation of the dissolution rate and peak time showed significant linear relationship respectively. From the results of this experiment, it can be concluded that the bioavailability of aspirin tablets showed much difference according to commercial preparations, and that the bioavailability of aspirin tablets in human may be predicted from the results of dissolution rate studies.

• Archives of Pharmacal Research
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• v.29 no.4
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• pp.333-338
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• 2006

The aim of this study was to investigate the effect of morin on the bioavailability of nimodipine after administering nimodipine (15 mg/kg) orally to rabbits either co-administered or pretreated with morin (2, 10 and 20 mg/kg). The plasma concentrations of nimodipine in the rabbits pretreated with morin were increased significantly (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg) compared with the control, but the plasma concentrations of nimodipine co-administered with morin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations $(C_{max})$ of the nimodipine in the rabbits pretreated with morin were significantly higher (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg), but only the $C_{max}$ of nimodipine coadministered with morin 10 mg/kg was increased significantly (p<0.05). The absolute bioavailability $(A.B\%)$ of nimodipine in the rabbits pretreated with morin was significantly (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg) higher $(54.1-65.0\%)$ than the control $(36.7\%)$. The increased bioavailability of nimodipine in the rabbits pretreated with morin might have been resulted from the morin, which inhibits the efflux pump P-glycoprotein and the first-pass metabolizing enzyme by cytochrome P-450 3A4 (CYP 3A4).