• Journal of Pharmaceutical Investigation
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• 제28권4호
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• pp.257-266
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• 1998

To improve the solubility and dissolution rate of acyclovir (ACV), which is low oral bioavailability due to its properties of slight solubility in water and incomplete gastrointestinal absorption, the solid inclusion complexes of ACV with ${\alpha}CD$, ${\beta}CD$, $DM{\beta}CD$ in molar ratio of 1:1 were prepared by the freeze-drying method. The inclusion complexes were investigated by solubility study, UV, IR and DSC. The dissolution rate of ACV was significantly increased by ACV-CDs inclusion complex formation in artificial intestinal fluid at pH 6.8. The enhanced dissolution rate of ACV could be due to an increase of solubility and the formation of an amorphous structures through inclusion complexation with CDs. Especially, $ACV-DM{\beta}CD$ inclusion complex enhanced the maximum plasma concentration levels and AUC following oral administration compared to those of ACV alone. The present results suggest that $ACV-DM{\beta}CD$ inclusion complex serves as a potential carrier for improving the solubility, the dissolution rate and the bioavailability of ACV.

• Biomolecules & Therapeutics
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• 제5권3호
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• pp.272-277
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• 1997

The effect of nonionic surfactant(polyoxyl 40 hydrogenated castor oil, PHCO), a common solubi-lizer, on the solubility of silymarin in the combined preparation containing ursoseoxycholic acid(UDCA) and silymarin was investigated in vivo using HPLC. The solubility of silybin, a major component of silymarin, was enhanced by increasing the amount of PHCO. The effect of PHCO on bioavailability was also evaluated in rats. The bioavailability was calculated by silybin content in bile juice that was excreted for 24 hr after oral administration. It was found that the bioavailability of silymarin containing PHCO was significantly increased compared to that of control. These results suggest that PHCO may improve the solubility and bioavailabilty of silymarin when it is combined with UDCA and silymarin.

• Journal of Pharmaceutical Investigation
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• 제32권4호
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• pp.299-303
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• 2002

The oral bioavailability of itraconazole is variable and low in fasting state. This is mainly due to the low solubility of this drug. Bioavailability can be improved by changing the formulation and it is general that the liquid preparations show greater bioavailability than the solid dosage forms such as tablets and capsules do. Benzyl alcohol-water binary mixture showed the excellent solubilizing capacity for itraconazole but the release of the drug from the preparation needs to be enhanced. In this study, various nonionic surfactants and hydrophilic polymers, poloxamers, were screened to investigate their effects on the releasε of itraconazole from the liquid preparations. Poloxamer 407 showed the most enhancing effect on the drug release and the release rate was proportional to thε amount of poloxamer 407 added. A liquid preparation of itraconazole, consisting of benzyl alcohol/water/poloxamer 407 ternary solvent system, releasεd more than 80% of the total drug amount at 5 min and showεd the possibility of a new formulation development.

• Biomolecules & Therapeutics
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• 제19권4호
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• pp.493-497
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• 2011

The aim of this study was to investigate the effect of amlodipine 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 amlodipine (0.1 or 0.4 mg/kg) in rats. The effect of amlodipine on the P-glycoprotein (P-gp) as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Amlodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 9.1 ${\mu}M$. Compared to those animals in the oral control group (warfarin without amlodipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (0.1 mg/kg, p<0.05; 0.4 mg/kg, p<0.01) by 26.5-53.5%, and the peak plasma concentration ($C_{max}$) was significantly higher (0.4 mg/kg, p<0.05) by 26.2% after oral administration of warfarin with amlodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.26- to 1.53-fold and the absolute bioavailability of warfarin with amlodipine was significantly greater by 61.7-72.5% compared to that in the control group (47.4%). In contrast, amlodipine 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 rather than renal elimination and P-gp by amlodipine.

• Preventive Nutrition and Food Science
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• 제14권3호
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• pp.201-207
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• 2009

In an effort to improve ginsenoside bioavailability, the ginsenosides of fermented red ginseng were examined with respect to bioavailability and physiological activity. The results showed that the fermented red ginseng (FRG) had a high level of ginsenoside metabolites. The total ginsenoside contents in non-fermented red ginseng (NFRG) and FRG were 35715.2 ${\mu}g$/mL and 34822.9 ${\mu}g$/mL, respectively. However, RFG had a higher content (14914.3 ${\mu}g$/mL) of ginsenoside metabolites (Rg3, Rg5, Rk1, CK, Rh1, F2, and Rg2) compared to NFRG (5697.9 ${\mu}g$/mL). The skin permeability of RFG was higher than that of NFRG using Franz diffusion cells. Particularly, after 5 hr, the skin permeability of RFG was significantly (p<0.05) higher than that of NFRG. Using everted instestinal sacs of rats, RFG showed a high transport level (10.3 mg of polyphenols/g sac) compared to NFRG (6.67 of mg of polyphenols/g sac) after 1 hr. After oral administration of NFRG and FRG to rats, serum concentrations were determined by HPLC. Peak concentrations of Rk1, Rh1, Rc, and Rg5 were approximately 1.64, 2.35, 1.13, and 1.25-fold higher, respectively, for FRG than for NFRG. Furthermore, Rk1, Rh1, and Rg5 increased more rapidly in the blood by the oral administration of FRG versus NFRG. FRG had dramatically improved bioavailability compared to NFRG as indicated by skin permeation, intestinal permeability, and ginsenoside levels in the blood. The significantly greater bioavailability of FRG may have been due to the transformation of its ginsenosides by fermentation to more easily absorbable forms (ginsenoside metabolites).

• Biomolecules & Therapeutics
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• 제18권1호
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• pp.106-110
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• 2010

The pharmacokinetics and bioavailability of ambroxol, an expectoration improver and mucolytic agent, were studied to determine the feasibility of enhanced transdermal delivery of ambroxol from the ethylene-vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether as an enhancer in rats. The ambroxol-010 matrix system (15 mg/kg) was applied to abdominal skin of rats. Blood samples were collected via the femoral artery for 28 hrs and the plasma concentrations of ambroxol were determined by HPLC. Pharmacokinetic parameters were calculated using Lagran method computer program. The area under the curve (AUC) was significantly higher in the enhancer group ($1,678{\pm}1,413.3\;ng/ml{\cdot}hr$) than that in the control group $1,112{\pm}279\;ng/ml{\cdot}hr$), that is treated transdermally without enhancer, showing about 151% increased bioavailability (p<0.05). The average $C_{max}$ was increased in the enhancer group ($86.0{\pm}21.5\;ng$/ml) compared with the control group ($59.0{\pm}14.8\;ng$/ml). The absolute bioavailability was 13.9% in the transdermal control group, 21.1% in the transdermal enhancer group and 18.1% in the oral administration group compared with the IV group. The $T_{max}$, $K_a$, MRT and $t_{1/2}$ of ambroxol in transdermal enhancer group were increased significantly (p<0.01) compared to those of oral administration. As the ambroxol-EVA matrix containing polyoxyethylene-2-oleyl ether and tributyl citrate was administered to rats via the transdermal routes, the relative bioavailability increased about 1.51-fold compared to the control group, showing a relatively constant, sustained blood concentration. The results of this study show that ambroxol-EVA matrix could be developed as a transdermal delivery system providing sustained plasma concentration.

• Journal of Pharmaceutical Investigation
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• 제18권2호
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• pp.61-67
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• 1988

The influence of different suppository bases on the dissolution, and the bioavailability of aspirin suppositories in rabbits and humans was investigated using Witepsol H15 (WIT), WIT-Tween 80 (TWE), WIT-sodium lauryl sulfate (SLS), polyethylene glycol (PEG), hollow WIT (WIT-HOLL) and capsule incorporated into WIT (WIT-CAP). The results obtained were as follows: 1) Dissolution rates of aspirin suppositories with different bases in distilled water were faster in the order of WIT-TWE >WIT-SLS >PEG >WIT-HOLL >WIT >WIT-CAP. 2) The maximum blood levels $(C_{max})$ of aspirin in rabbits and humans were highest in WIT-TWE and WIT-SLS bases, but $C_{max}$ from WIT base was lower than that in oral administration of aspirin suspension. 3) The times reaching the maximum blood levels $(T_{max})$ in rabbits were 1 hr for oral administration, 1.5-2.5 hr for WIT-TWE, WIT-SLS, PEG, and WIT bases, and 2.5-4.0 hr for WIT-HOLL and WIT-CAP bases, but $T_{max}$ in humans were 1 hr for oral administration and WIT-TWE base, and 2-4 hr for WIT and WIT-HOLL bases. 4) Relative bioavailability (RBA) of aspirin suppositories in rabbits was higher in WIT-SLS, WIT-TWE and PEG bases than that in oral administration, and RBA of aspirin suppositories in humans was higher in the order of WIT-TWE >PEG >WIT-HOLL >oral >WIT bases tested. 5) Good correlation between dissolution rates and $C_{max}$ was obtained: y = 0.60x+32.23 (r = 0.96) for rabbits, and y = 0.60x+35.74 (r = 0.97) for humans.

• 한국임상약학회지
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• 제23권3호
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• pp.206-212
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• 2013

Purpose: The aim of this study was to investigate the effect of nimodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Methods: Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of nimodipine (0.5 or 2 mg/kg) in rats. The effect of nimodipine on the P-glycoprotein as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Results: Nimodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $10.2{\mu}M$. Compared to those animals in the oral control group (warfarin without nimodipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (0.5 mg/kg, P<0.05; 2 mg/kg, P<0.01) by 31.3-57.6%, and the peak plasma concentration ($C_{max}$) was significantly higher (2 mg/kg, P<0.05) by 29.4% after oral administration of warfarin with nimodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.31- to 1.58-fold and the absolute bioavailability of warfarin with nimodipine was significantly greater by 64.1-76.9% compared to that in the control group (48.7%). In contrast, nimodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Conclusion: Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism rather than P-glycoprotein-mediated efflux by nimodipine.

• Journal of Pharmaceutical Investigation
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• 제25권1호
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• pp.19-29
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• 1995

The study was carried out to develop useful formulation for omeprazole(OMP) through OMP-ethylendiamine complex(OMPED), and the pharmaceutical properties of formula were tested to find out the difference in vivo behaviors of formulations between the free and complexed OMP. Oral and suppository dosage forms were also formulated and the dissolution profiles and pharmacokinetic parameters were measured to observe the difference in bioavailability between the free and complex form, and the correlation between dissolution rate and bioavailability was evaluated. The results are summarized as follows; In the case of formulation for oral administration, the release of OMP from enteric OMPED pellets was found satisfactory to the requirement standard and no decomposition of OMP in the pellets was found in acidic solution. Therefore the enteric OMPED pellets are anticipated to be a stable formulation. The release of OMP from OMPED tablet with chitosan as excipient and coated with cellulose acetate phthalate was found to be significantly retarded. The results of bioavailability test for OMP and OMPED tablets with lactose-excipient showed that the AUC value of OMP tablet was $116.89\;{\mu}g\;{\cdot}\;min/ml$, that of OMPED tablet was $161.10\;{\mu}g\;{\cdot}\;min/ml$, respectively. The reason why was thought that OMP decomposes more readily in body than OMPED, and the AUC of the tablet with chitosan-excipient and coated with cellulose acetate phthalate was most enhanced. In the case of bioavailability for suppositories with OMP, $OMP-{\beta}\;-cyclodextrin$ complex and OMPED, the AUC of OMPED suppository was most increased. From the above results, it is thought that the more stable and bioavailable oral or rectal dosage forms could be developed by using the OMPED as a potential OMP complex.

• Journal of Pharmaceutical Investigation
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• 제20권1호
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• pp.29-33
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• 1990

Plasma and saliva concentrations of acetaminophen (AAP) were determined at various time points by HPLC after oral administration of AAP tablets (AAP 500 mg) to four healthy male Korean subjects. Saliva concentrations (S) of AAP were significantly correlated with plasma AAP concentrations (P). The S/P ratio of AAP was calculated to be 1.05 (r =0.944, $p<10^{-6}$) for all the data points from the subjects. It showed a little intersubject variation and ranged from 0.89 to 1.46 in each subject. Bioavailability parameters such as AUC, $C_{max}$ and $T_{max}$ which are usually obtained from the plasma concentration data will be predictable approximately by saliva concentration data. Saliva seems to be very convinient and useful samples for the preliminary studies of bioavailability and bioequivalence of AAP preparations, since it can be collected frequently without any painful venipuncture to the subjects, that is inevitable in plasma sampling. Evaluation of the bioavailability of a preparation by saliva samples will reduce the cost, time and safety risk greatly in developing a new drug delivery system for AAP.