• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.301-307
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• 2011

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $17.1{\mu}M$. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve ($AUC_{0-\infty}$) and the peak plasma concentration ($C_{max}$) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was significantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimodipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol.

• 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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• 제28권4호
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• pp.275-282
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• 1998

In order to develop a desirable in vitro release which correlates well with in vivo bioavailability, hollow type suppository containing Propranolol HCl(PPH) powder in the cavity and conventional type suppository with dispersed PPH in the base were prepared. Polyvinyl alcohol (PVA) hydrogel as a base and PPH as a model drug were used for the preparation of suppository. The rates of drug release from the suppositories were studied by Paddle method, Muranish method, Dialysis tubing method and Rotating dialysis cell method. The release profiles from suppositories using the four different release tests were compared. After a rectal administration in rat, the mean $C_{max}$ of hollow type suppository was significantly lower than that of conventional type, but $T_{max}$, $AUC_{0{\to}12}$ and MRT of hollow type were significantly higher 1.6 times, 1.2 times and 1.9 times than those of conventional type, respectively. The computer program was used to simulate plasma concentration from in vitro released amounts of drug and in vivo pharmacokinetic parameters. Based on comparison of the simulated bioavailability from computer program with experimental bioavailability in rat we have found out in vitro release test which correlates well with in vivo bioavailability. Our results have shown the best correlation between in vitro release and in vivo bioavailability in PPH-PVA hydrogel hollow type suppository for the paddle method and conventional type suppository for the rotating dialysis cell method. In this work we propose that PPH-PVA hydrogel suppository shows in vitro-in vivo correlation. This data should help to optimize the formulation of the drug and provide a basis for quality control procedures.

• 약학회지
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• 제49권3호
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• pp.230-236
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• 2005

The purpose of this study was to investigate the effect of naringin pretreatment on the bioavailability and phar-macokinetics of diltiazem and one of its metabolites, deacetyldiltiazem, in rabbits. Pharmacokinetic parameters of diltiazem and deacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) pretreated with naringin (1.5, 7.5 and 15 mg/kg). Absorption rate constant ($k_a$) of diltiazem after oral administration of diltiazem pretreated with naringin was significantly (p<0.05 or p<0.0l) increased compared to the control group. Area under the plasma concentration-time curve (AUC) and peak concentration ($C_{max}$) of the diltiazem were significantly (p<0.05 or p<0.01) higher than those of the control. Absolute bioavailability ($AB\%$) of diltiazem pretreated with naringin ranged from $13.5\%$ to $18.6\%$, being enhanced compared to that of the control, $7.2\%$. Relative bioavailability ($RB\%$) of diltiazem was $1.9\~2.6$ times higher than that of the control group. There was no significant change in terminal half-life ($t_{1/2}$) and $T_{max}$ of diltiazem in the presence of naringin. AUC of deacetyldiltiazem pretreated with naringin was significantly (p<0.05) higher than (p<0.05) that of the control. But the metabolite ratios (MR) were significantly decreased (p<0.05), implying that pretreatment of naringin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. In this study, pretreatment of naringin significantly enhanced the oral bioavailability of diltiazem. These results suggested that the diltiazem dosage should be adjusted when it is administered with naringin or a naringin-containing dietary supplement in the clinical setting.

• Biomolecules & Therapeutics
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• 제16권3호
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• pp.210-214
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• 2008

The pharmacokinetic parameters and bioavailability of pranoprofen from the gel were measured to determine the enhancing effect of octanoic acid on the transdermal absorption of pranoprofen in rats. 8 mg/kg of pranoprofen was administered from gel with octanoic acid (the enhancer group) or that without octanoic acid (the control group) via the transdermal route, and the results were compared with those obtained from the intravenously (0.5 mg/kg, IV group) or orally administered group (4 mg/kg, oral group). The AUC of the control, the enhancer, the IV, and the oral groups were $20.2{\pm}5.1$, $50.7{\pm}12.7$, $19.9{\pm}2.5$, and $70.5{\pm}17.6\;ug/ml{\cdot}h$ respectively. The average $C_{max}$ of the control and the enhancer group were $0.93{\pm}0.23$ and $2.82{\pm}0.71\;ug/ml$, respectively, and the mean $T_{max}$ of the control and the enhancer group was 7.00 h. The relative bioavailability of the transdermally administered pranoprofen gel containing octanoic acid was approximately 2.50 times higher than the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. This suggests that it might be feasible to develop a pranoprofen gel preparation containing an enhancer for the transdermal administration, which is more convenient dosage form than the oral dosage forms.

• 한국지하수토양환경학회:학술대회논문집
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• 한국지하수토양환경학회 2002년도 총회 및 춘계학술발표회
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• pp.18-21
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• 2002

Phytoremediation which uses plants to enhance the bioremediation through stimulation of microbial activity and root uptake, has been a topic of increasing interest. Mathematical model were developed that can be applied to various bioremediation methods in the unsaturated zone, especially phytoremediation, for simulating the fate and transport of contaminants under field conditions. A 2-year field study was conducted using 72 (1.5m long and 0.1 m diameter) column lysimeters with four treatments: Johnsongrass; wild rye grass; a rotation of Johnsongrass and wild rye grass; and unplanted fallow conditions. The developed model represented the fate and transport of contaminant both in vegetated and unplanted soils satisfactorily for field applications. Parameters related to the contaminant concentration in the water phase were the main parameters determining the contaminant fate in the vadose zone and indicated that the bioavailability can be the most important factor in the success of phytoremediation as well as bioremediation applications.

• 약학회지
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• 제50권5호
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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.

• Archives of Pharmacal Research
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• 제28권4호
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• pp.488-492
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• 2005

The purpose of this study is to investigate the bioequivalence of two haloperidol 5 mg tablets, Myung In haloperidol (Myung In Pharm. Co., Ltd., test drug) and $Peridol^{R}$(Whanin Pharm. Co., Ltd., reference drug), and also to estimate the pharmacokinetic parameters of haloperidol in Korean volunteers. The bioavailability and pharmacokinetics of haloperidol tablets were examined on 24 healthy volunteers who received a single oral dose of each preparation in the fasting state in a randomized balanced 2 way crossover design. After an oral dosing, blood samples were collected for a period of 60 h. Plasma concentrations of haloperidol were determined using a liquid chromatographic electrospray mass spectrometric (LC-MS) method. The pharmacokinetic parameters were calculated with noncompartmental pharmacokinetic analysis. The geometric means of $AUC_{0-60h} and C_{max}$ between test and reference formulations were $17.21\pm8.26 ng\cdot/mL vs 17.31\pm13.24 ng\cdot/mL and 0.87\pm0.74 ng/mL vs 0.85\pm0.62 ng/mL$. respectively. The $90\%$ confidence intervals of mean difference of logarithmic transformed $AUC_{0-60h} and C_{max} were log0.9677{\sim}log1.1201 and log0.8208{\sim}log1.1981$, respectively. It shows that the bioavailability of test drug is equivalent with that of reference drug. The geometric means of other pharmacokinetic parameters ($AUC_{inf}. t_{1/2}, V_{d}/F, and CL/F$) between test drug and reference drug were $21.75\pm8.50 ng{\cdot}h/mL vs 21.77\pm15.63 ng{\cdot}h/mL, 29.87\pm8.25 h vs 29.60\pm7.56 h, 11.51\pm5.45 L vs 12.90\pm6.12 L and 0.26\pm0.09 L/h vs 0.31\pm0.17 L/h$, respectively. These observations indicate that the two formulation for haloperidol was bioequivalent and, thus, may be clinically interchangeable.

• Journal of Pharmaceutical Investigation
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• 제33권3호
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• pp.201-208
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• 2003

Pharmacokinetics and oral bioavailability of levosulpiride was determined in Korean healthy male volunteers. Thirty subjects received a single oral dose (25 mg) of a tablet in a randomized $2{\times}2$ cross-over design. The plasma concentrations of levosulpiride were measured by HPLC and compared with those reported in the literature. Pharmacokinetic parameters for $Isomeric^{\circledR}$ tablet (levosulpiride 25 mg) were revealed as follows: $AUC_{inf}\;737.1{\pm}176.9\;ng{\cdot}hr/ml,\;C_{max}\;56.4{\pm}20.1\;ng/ml,\;T_{max}\;4.2{\pm}1.6\;hr,\;K_a\;1.00{\pm}1.09\;hr^{-1},\;K_{el}\;0.08{\pm}0.02\;hr^{-1},\;and\;t_{1/2}\;8.8{\pm}1.9\;hr$. The rate constant of the absorption phase was obtained based on the first-order kinetics. In the aspect of bioavailability, $Isomeric^{\circledR}$ tablet was bioequivalent to the other product $(Levopride^{\circledR}\;tablet)$ available in the Korea market. Intersubject variations and race differences were show in comparison with the published data in the literature, even though there was a linear relationship between dose ad extent of bioavailability.

• Biomolecules & Therapeutics
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• 제18권1호
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• pp.99-105
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• 2010

The purpose of this study was to evaluate relative bioavailability of the coenzyme Q10 (CoQ10) in emulsion and three liposome formulations after a single oral administration (60 mg/kg) into rats. Emulsion formulation of CoQ10 was prepared by conventional method using Phospholipon 85G as an emulsifier, and three liposome formulations (neutral, anionic, and cationic) of CoQ10 were prepared by traditional lipid film hydration technique using Phospholipon 85G, cholesterol, and charge carrier lipids (1,2-dioleoyl-3-trimethylammonium-propane chloride salt for cationic liposome and 1,2-dimyristoyl-sn-glycero-3-phosphate monosodium salt for anionic liposome). Mean particle size of all CoQ10-loaded liposome was less than a micron, and size distribution of the liposome population was homogeneous. Bioavailability of CoQ10 in emulsion was 1.5 to 2.6-fold greater than liposome formulations in terms of $AUC_{0-24\;h}$. $T_{max}$ was 3 h when administered as emulsion while it was greater than 6 h in liposome formulations. Notably, it was approximately 8 h in cationic liposome. $C_{max}$ was highest in emulsion and was significantly decreased when administered as liposome. Charged liposome showed even lower $C_{max}$ than neutral liposome, especially in cationic liposome. In conclusion, therefore, it is suggested that clinicians and patients consider bioavailability issue a primary concern when choosing a CoQ10 product, especially when very high plasma level is required such as in the treatment of heart failure and Parkinson's disease.