• The Journal of Korean Medicine
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• v.38 no.2
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• pp.61-72
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• 2017

Objectives: The effects of Gamiondam-tang (GMODT) co-administration within 5min on the pharmacokinetics (PK) of tamoxifen were observed as a process of the comprehensive and integrative medicine, combination therapy of tamoxifen with GMODT to achieve synergic pharmacodynamics and reduce toxicity on the breast cancer. Methods: After 50mg/kg of tamoxifen treatment, GMODT 100mg/kg was administered within 5min. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of GMODT treatment, and plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. PK parameters of tamoxifen (Tmax, Cmax, AUC, $t_{1/2}$ and $MRT_{inf}$) were analysis as compared with tamoxifen single administered rats using noncompartmental pharmacokinetics data analyzer programs. Results: Co-administration with GMODT induced increased trends of plasma tamoxifen concentrations to 1hr after end of administration, and then showed decreased trends of plasma tamoxifen concentrations, and especially significant (p<0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5hr after end of co-administration with GMODT and also related significant (p<0.05) decreases of $AUC_{0-inf}$ and $MRT_{inf}$ as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 10 mg/kg and GMODT 100 mg/kg within 5 min, in this experiment. Conclusion: Based on the results of the present study, it is considered that single co-administration GMODT within 5min significantly inhibited the oral bioavailability of tamoxifen through variable influences on the absorption and excretion of tamoxifen, can be influenced on the toxicity or pharmacodynamic of tamoxifen.

• Biomolecules & Therapeutics
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• v.16 no.3
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• pp.215-218
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• 2008

To investigate the possible interaction between rutaecarpine and phenobarbital in rats, phenobarbital in saline at 80 mg/kg was given ip to male SD rats for 3 consecutive days. Saline was given to control animals. One day after phenobarbital pre-treatment, rutaecarpine at 16 mg/kg was administered through penile vein. Blood was collected and analyzed by using HPLC. The pharmacokinetic parameters were determined with the non-compartmental model. Pre-treatment with phenobarbital significantly altered the pharmacokinetic profiles of rutaecarpine and its metabolite, 10-hydroxyrutaecarpine. The AUC of rutaecarpine was reduced to approximately 50% of control and the plasma half-life of rutaecarpine was significantly shortened when compared with control. In addition, the Cmax of 10-hydroxyrutaecarpine was increased approximately 160% of control. The AUC and the plasma half-life of 10-hydroxyrutaecarpine were decreased to 76.9% of control and to 82.7 min from 175.9 min, respectively. The results suggested that phenobarbital might accelerate the metabolism of rutaecarpine, thereby changing the pharmacokinetic parameters of rutaecarpine in male SD rats.

• Journal of Pharmaceutical Investigation
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• v.41 no.5
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• pp.273-278
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• 2011

The aim of this study was to investigate the effect of efonidipine 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 efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine 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 and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

• Biomolecules & Therapeutics
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• v.18 no.1
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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.

• Toxicological Research
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• v.17 no.4
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• pp.317-323
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• 2001

The skin penetration rate of methidathion in vitro and pharmacokinetics of methidathion in vivo were studied with male Sprague-Dawley rats by dermal treatment. The in vitro skin penetration rates for Sprague-Dawley rats of methidathion technical (50 mg, 100 ${mu}ell$) and emulsifable concentrate (EC,40mg, 100${mu}ell$) were determined as 18.4 $\mu\textrm{g}$/c $m^2$/h (RSD : 6.5) and 18.5 $\mu\textrm{g}$/c $m^2$/h (RSD : 3.2), respectively. Dose-related systemic exposure (AUC) was observed in rats after dermal treatment. The corresponding AUC, $T_{max}$, $C_{max}$, and $T_{1}$2/ of methidathion in plasma were 1.5$\mu\textrm{g}$.hr/ml, 6 h, 0.10 $\mu\textrm{g}$/ml, and 16 h, for 116mg/kg doses, 3.2 $\mu\textrm{g}$. hr/ml, 8 h, 0.12 $\mu\textrm{g}$/ml, and 23 h, for 232 mg/kg doses and 10 $\mu\textrm{g}$. hr/ml, 12 h, 0.32 $\mu\textrm{g}$/ml, and 20 h, for 1,160 mg/kg doses respectively. The urinary excretion of methidathion, estimated wing an equation derived from the in vitro skin penetration study was 0.24~0.35% of the absorbed dose. The concentration of methidathion in kidney was higher than that in liver. Dose-dependent absorption and excretion of methidathion without saturation was observed under in vivo experimental condition.n.n.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.648-658
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• 2017

7-O-Succinyl macrolactin A (SMA) exerts several pharmacological effects including anti-bacterial, anti-inflammation, and anti-cancer activities. Recently, SMA has been extensively evaluated as an anti-cancer drug. Thus, the objectives of the present study were to characterise the pharmacokinetics of SMA via both non-compartmental and compartmental analysis in mice, rats, and dogs, and to derive an appropriate first-in-man dose based on allometric scaling of the animal data. The time courses of plasma SMA concentrations after intravenous administration to rats and dogs were analysed retrospectively, as were data collected after intraperitoneal SMA injection in mice. Pharmacokinetic parameters were estimated via both noncompartmental and compartmental analysis, and were correlated with body weight and/or the potential maximum life-span. The clearance and distribution volume of SMA in humans were predicted, and a first-in-man dose proposed. A two-compartment model best described the time courses of SMA plasma concentrations after a saturation elimination process was applied to fit the dataset obtained from rats. Incorporation of the maximum potential life-span during allometric scaling was required to improve the estimation of human clearance. The SMA clearance and the distribution volume in the steady state, in a 70-kg adult male, were estimated to be 30.6 L/h and 19.5 L, respectively. To meet the area under the curve (AUC) required for anti-tumour activity, a dose of 100 mg (~1.5 mg/kg) was finally proposed as the first dose for a 70-kg human. Although toxicological profiles derived from non-clinical studies must be considered before any final decision is made, our work will facilitate clinical studies on SMA.

• YAKHAK HOEJI
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• v.42 no.4
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• pp.431-436
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• 1998

The pharmacokinetics of CKD-602, a new camptothecin anticancer derivative, were studied in mice, rats and dogs following a single or multiple intravenous administration, and the following results were obtained. The blood levels of CKD-602 declined in biphasic fashions with peak plasma levels $(C_0)$ of $2.63{\mu}g/ml$ in mice, $2.27{\mu}g/ml$ in tumor bearing mice, $2.84{\mu}g/ml$ in rats at a dose of 20mg/kg, and of 0.02mcg/ml in dogs at a dose of 0.5mg/kg. The plasma half-lives $(t_{1/2}{\beta})$ were 9.55hr in mice, 9.94hr in tumor bearing mice, 9.98hr in rats and 12.75hr in dogs. AUC of CKD-602 was increased linearly with the dose at a range from 5 to 20mg/kg. Moreover, Cltot and Vdss were also not significantly changed with increasing the dose. On the other hand, after 5 daily intravenous bolus injection of CKD-602 (5mg/kg) in rats, $t_{1/2}{\beta}$, AUC and MRT of CKD-602 were 11.90hr, $3.19{\mu}g{\cdot}hr/ml$, and 11.61hr, respectively, which were slightly higher than after the single bolus injection.

• YAKHAK HOEJI
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• v.28 no.4
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• pp.207-215
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• 1984

Effects of Ssang Wha Tang (SWT), a blended Chinease traditional medicine, on the pharmacokinetics of sulfobromophthalein (BSP) in the rats of hepatic failure induced by carbon tetrachloride were examined. The disposition of plasma BSP in carbon tetrachloride-treated rats (Group I) and in carbon tetrachloride+SWT-treated rats (Group II) followed a three-compartment model, while those in control group followed two-compartment model. GOT, GPT level and some pharmacokinetic paramiters like plasma clearance but except distribution volume (Vdss) recovered in Group II compared to Group I. Therefore, SWT seemed to have an apparent restoring effect of hepatic function damaged by carbon tetrachloride treatment. From the fact that Vdss of BSP in Group II was considered as an one of the probable mechanisms. More intensive increase in BSP-free fraction ($f_p$) in Group II than that in Group I might also explain the increases of BSP clearance and Vdss in Group II compared to Group I. Assuming no changes in hepatic plasma flow(Q) in each group, hepatic intrinsic clearance($CL^h_{int}$) decreased in Group I did not recovered not at all in Group II. Therefore SWT seemed not to have any restoring effect of true hepaticfunction to biotransform and excrete BSP, and the apparent restoring effect of SWT might be due only to the replacement of BSP-plasma protein binding. Whether $f_p$ is actually higer in Group II than in Group I, and Q is constant in each group are being examined in our laboratory. The changes of Q, which might lead to another conculusions, also should be taken into consideration to clarify the apparent hepatorestoring effect of SWT.

• Biomolecules & Therapeutics
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• v.19 no.4
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• pp.498-503
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• 2011

The purpose of this study was to investigate the effects of nisoldipine on the pharmacokinetics of repaglinide in rats. The effect of nisoldipine on cytochrome P450 (CYP) 3A4 activity and P-glycoprotein (P-gp) were evaluated. The pharmacokinetic parameters of repaglinide were also determined in rats after oral (0.5 $mg{\cdot}kg^{-1}$) and intravenous (0.2 $mg{\cdot}kg^{-1}$) administration of repaglinide to rats without or with nisoldipine (0.3 and 1.0 $mg{\cdot}kg^{-1}$). Nisoldipine inhibited CYP3A4 enzyme activity with a 50% inhibition concentration of 5.5 ${\mu}M$. In addition, nisoldipine significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, nisoldipine significantly increased the $AUC_{0-{\infty}}$ and the $C_{max}$ of repaglinide by 46.9% and 24.9%, respectively. Nisoldipine also increased the absolute bioavailability (A.B.) of repaglinide by 47.0% compared to the oral control group. Moreover, the relative bioavailability (R.B.) of repaglinide was 1.16- to 1.47-fold greater than that of the control group. Nisoldipine enhanced the oral bioavailability of repaglinide, which may be attributable to the inhibition of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and to inhibition of P-gp in the small intestine rather than to reduction of renal elimination of repaglinide by nisoldipine. The increase in the oral bioavailability of repaglinide should be taken into consideration of potential drug interactions when co-administering repaglinide and nisoldipine.

• Journal of Pharmaceutical Investigation
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• v.29 no.1
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• pp.21-27
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• 1999

Semi-solid poly(ortho esters) (POE) were prepared to provide bioerodible carriers for sustained drug delivery systems of naloxone (NLX) in the treatment of narcotic addiction. As the POE have viscous behavior at room temperature, a significant advantage of this polymer is that it can be injected without any surgical intervention. The POE was synthesized by a transesterification reaction between 1,2,6-hexanetriol and trimethyl orthoacetate, and the structure of the polymer was confirmed by IR. The in vitro release of the drug from POE was studied. The release rate of NLX decreased with increasing intrinsic viscosities of the polymer. In vivo biocompatibility studies were carried out in rats with NLX loaded POE. Histopathological analysis showed that NLX implants are well-tolerated by rats when used subcutaneously. Pharmacokinetic studies of POE-NLX implants of two different viscosities were carried out in rabbits. In all cases, plasma concentrations of NLX were maintained over 1 ng/ml for at least 168 hours, but initial burst effect was observed. Mean residence time(MRT) was found to depend on the viscosity of the polymer.