• Journal of Pharmaceutical Investigation
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• 제29권2호
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• pp.99-103
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• 1999

Self-Emulsifying System(SES), an isotropic mixture of oil and surfactant which forms oil-in-water emulsion, is expected to improve in vitro drug dissolution and enhance in vivo drug absorption. A poorly water soluble drug, ibu-profen(IBP) was incorporated into the SES to improve absorption, and enhance bioavailability of drug. Medium chain triglyceride, glyceryl tricaprylate(GTC) as an oil, and Tween 85 as a surfactant were used to formulate SES. To characterize SESs with various concentrations of Tween 85, the phase separation and solubility of IBP-SEDDS containing IBP as a function of Tween 85 concentration were conducted, and the particle size was measured using photon correlation spectroscopic method. The SES with optimal concentration of Tween 85(35%(w/w)) was selected based on its high drug loading, small particle size and low surfactant concentration. After an oral administration of IBP-SEDDS and IBP suspension in methyl cellulose equivalent to 40.0 mg/kg to rats, the pharmacokinetic parameters were compared. The $C_{max}(163.17\;vs\;88.82\;{\mu}g/ml)$, $AUC(12897.01\;vs\;8751.13\;{\mu}g\;min/ml)$ and Bioavailability(86.44 vs 58.65%) significantly increased but $T_max(10\;vs\;20\;min)$ was significantly advanced. The current SEDDS containing IBP provide an alternative to improve an oral bio-availability of IBP.

• 약학회지
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• 제51권3호
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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.

• 한국임상약학회지
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• 제18권1호
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• pp.6-10
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• 2008

This study investigated the effect of long-term administration of pioglitazone on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats coadministered pioglitazone (0.5 mg/kg) or pretreated with pioglitazone (0.5 mg/kg) for 3 and 9 days. Compared to oral control group, the presence of pioglitazone significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of verapamil by 48.6% (coad), 61.1% (3 days) and 56.5% (9 days), and the peak concentration($C_{max}$) by 65.1% (coad), 76.8% (3 days) and 66.4% (9 days). The absolute bioavailability (AB%) of verapamil was significantly (p<0.05) higher by 6.2% (coad), 6.7% (3 days), 6.5% (9 days) compared to control (4.2%), and presence of pioglitazone was no significant change in the terminal half-life ($t_{1/2}$) and the time to reach the peak concentration($T_{max}$) of verapamil. Our results indicate that pioglitazone significantly enhanced oral bioavailability of verapamil in rats, implying that presence of pioglitazone could be effective to inhibit the CYP3A4-mediated metabolism of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with pioglitazone.

• 약학회지
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• 제48권1호
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• pp.1-5
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• 2004

The purpose of this study was to investigate the effect of coadministration and 3 days-pretreatmemt of niledipine (2, 10 mg/kg) on the pharmacokinetic parameters and bioavailability of paclitaxel (50 mg/kg) after oral administration in rats. Coadministration of nifedipine with paclitaxel did alter the $C_{max}$ (115${\pm}$29 ng/ml without nifedipine; 135${\pm}$35 ng/ml with nifedipine (10 mg/kg): p<0.05) and AUC (188${\pm}$459 ng/mlㆍhr with-out nifedipine; 2546${\pm}$642 ng/mlㆍhr with nifedipine; p<0.05). Three days treatment of nifedipine on the prior to paclitaxel administration increased the $t_{1/2}$ 〔9.90${\pm}$2.47 hr without nifedipine; 12.37${\pm}$3.12 hr with nifedipine (2 mg/kg): 12.83${\pm}$3.32 hr with nifedipine (10 mg/ml); p<0.05] and AUC [1833${\pm}$459 ng/mlㆍhr without nifedipine; 2663${\pm}$648 ng/mlㆍhr with nifedipine (2 mg/kg): 3006${\pm}$734 ng/mlㆍhr with nifedipine (10 mg/ml): p <0.05]. Drug interaction between nifedipine and paclitaxel decreased the elimination rate constant and increased the oral bioavailability of paclitaxel. On the basis of the results of this study, it might be considered that nifedip ine may inhibit cytochrome P450, which are engaged in paclitaxel metabolism, result in increased $t_{1/2}$ and AUC of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bio-availability wit/or without nifedipine.

• 약학회지
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• 제47권2호
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• pp.98-103
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• 2003

The purpose of this study was to investigate the effect of flavone (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with flavone was increased significantly (coadministration p＜0.05, pretreatment p＜0.0l) compared to that of control. Area under the plasma concentration-time curve (AVC) of paclitaxel with flavone was significantly (coadministration p＜0.05, pretreatment p＜0.0l) higher than that of control. Peak concentration (Cmax) of paclitaxel with flavone were significantly increased (coadministration p＜0.05, pretreatment p＜0.01) compared to that of control. Time to peak concentration (Tmax) of paclitaxel with flavone decreased significantly (p＜0.05) than that of control. The total body clearance (CLt) and elimination rate constant ($\beta$) of paclitaxel with flavone were significantly reduced (p＜0.05) compared to those of control. Half-life (t$_{1}$2/) of paclitaxel with flavone was significantly prolonged (p＜0.05) compared to that of control. Based on these results, it might be concluded that flavone may enhance bioavailability of paclitaxel through the inhibition of cytochrome P450 and P-glycoprotein, which are engaged in paclitaxel absorption and metabolism in liver and gastrogintestinal mucosa, respectively.

• 한국임상약학회지
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• 제19권1호
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• pp.32-36
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• 2009

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of nicardipine in rats. Pharmacokinetic parameters of nicardipine were determined after an oral administration of nicardipine (12 mg/kg) to rats coadministered with simvastatin (0.3 and 1.0 mg/kg). Compared with the control (given nicardipine alone), coadministration of simvastatin (1.0 mg/kg) significantly (p<0.05) increased the area under the plasma concentration (AUC) and peak plasma concentration ($C_{max}$) of nicardipine. The relative bioavailability (RB%) of nicardipine increased from 1.19- to 1.48-fold. However there were no significant changes in $t_{max}$, and $t_{1/2}$ of nicardipine. The enhanced oral bioavailability of nicardipine might be due to an inbition of cytochrom P450 3A mediated-metabolism of nicardipine in the intestine and in the liver by simvastatin. Based on these results, the concurrent use of simvastatin significantly enhanced the oral exposure of nicardipine in rats. The dosage regimen of nicardipine should be taken into consideration for potential drug interaction when combined with simvastatin in clinics.

• Journal of Pharmaceutical Investigation
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• 제30권2호
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• pp.113-118
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• 2000

In order to assay the efficacy of newly synthesized antiviral compounds, pyrimidine analogs, pharmacokinetics of those were established as compared with already marketed zidovudine. Zidovudine (15, 20, 25 and 35 mg/kg), LJ142 (18.52 mg/kg) and LJ143 (15, 18.52 and 30 mg/kg) were administered orally and intravenously in rats, blood samples were collected post-injection(i.e., for 360 min) at appropriate time intervals. Those were analyzed by HPLC with UV detection at 265 nm. Pharmacokinetic parameters $(C_{max},\;T_{1/2},\;MRT,\;AUC,\;AUMC,\;Vd_{SS},\;Cl_t)$ were calculated. AUCs of zidovudine and LJ143 following I.V. dosing of $15{\sim}25\;mg/kg\;and\;15{\sim}18.18\;mg/kg$ were dose-independent. However, AUCs of zidovudine and LJ43 following I.V. dosing of $25{\sim}35\;mg/kg\;and\;18.18{\sim}30\;mg/kg$ were dose-dependent. The relative bioavailability of zidovudine, LJ142 and LJ143 following oral administration were 61.94, 46.44 and 78.24%, respectively.

• Biomolecules & Therapeutics
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• 제19권2호
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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.

• Biomolecules & Therapeutics
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• 제2권4호
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• pp.310-315
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• 1994

The pharmacokinetics and tissue distribution of DA-3030 (recombinant human granulocyte colony-stimulating factor, rhG-CSF, recently manufactured by Dong-A research laboratory of Dong-A Pharmaceutical Company) were compared with reported data in the literature. After intravenous(i.v.) administration of DA-3030, at dose of 5, 10 and 100 $\mu\textrm{g}$/kg to rats, some pharmacokinetic parameters, such as terminal half-lives(1.05, 1.19 and 1.83 hr, respectively) and clearance (84.0, 54.8 and 45.5 mι/hr/kg, repectively), were dose-dependent. This could be due to the saturable metabolism of DA-3030 in rats. Similar results were also reported. After subcutaneous(s.c.) and intramuscular(i.m.) administrations of DA-3030, 10 $\mu\textrm{g}$/kg to rats, the extent of bioavailability(absolute bioavailability) were incomplete; the values were 23.3 and 18.2% after s.c. and i.m. injections, respectively, due to the degradation of DA-3030 by protease. After 7-consecutive day i.v. administrations of DA-3030, 10 $\mu\textrm{g}$/kg/day, to rats, the plasma concentrations and pharmacokinetic parameters of DA-3030 were not significantly different from those in single administration. In mice and dogs at DA-3030 dose of 10 $\mu\textrm{g}$/kg, the plasma concentrations of DA-3030 were also declined rapidly with terminal half-lives of 1.31 and 1.15 hr, respectively. DA-3030 was highly concentrated in the kidney after i.v. administration of DA-3030, 10 $\mu\textrm{g}$/kg, to rats, and the results were similar to those obtained using radiolabelled rhG-CSF in the literature. Above data indicate that DA-3030 has similar properties to rhG-CSF manufactured by other companies in view of pharmacokinetics.

• 대한한의학회지
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• 제41권4호
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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.