• 동의생리병리학회지
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• 제34권4호
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• pp.201-208
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• 2020

The effects of Gamisoyo-san (GMSYS) co-administration within 5 min on the pharmacokinetics (PK) of tamoxifen were observed. After 50 mg/kg of tamoxifen oral treatment, GMSYS 100 mg/kg was orally administered within 5 min to 7-wk old male SPF.VAF Outbred Crl:CD [Sprague-Dawley (SD)] rats. The plasma were 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. Tmax, Cmax, AUC, t1/2 and MRTinf of tamoxifen were analysis as compared with tamoxifen single administered rats. Although co-administration with GMSYS did not critically influenced on the pharmacokinetic parameters of oral tamoxifen, they induced increased trends of plasma tamoxifen concentrations, especially significant (p<0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5 hr after end of co-administration with GMSYS as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 10 mg/kg and GMSYS 100 mg/kg within 5 min. It is considered that pharmacokinetic studies should be tested like the effects of GMSYS on the pharmacokinetics of tamoxifen, when they were co-administered with prolonger intervals than Tmax of tamoxifen oral administration (about 2.5 hr-intervals), to achieve the optimal dosing regimen of GMSYS and tamoxifen co-administration.

• Journal of Pharmaceutical Investigation
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• 제37권6호
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• pp.369-376
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• 2007

Cyclosporine (CsA) and tacrolimus (FK506) have a narrow therapeutic range, and their pharmacokinetic (PK) characteristic varies among individual. They are also substrates for cytochrome P450 (CYP) 3A4, 3A5 genes, and P-glycoprotein, the product of the multidrug resistance 1 (MDR1). The aims were to investigate the relationship between CYP3A and MDR1 genotypes and their PK parameters among healthy subjects. We investigated the genotype for CYP3A and MDR1 gene in human using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. After oral administration of CsA and FK506 (100 mg and 1 mg, respectively), whole blood samples were taken up to 24 hours. Blood CsA and FK506 concentrations were measured by LC/MS/MS. Each PK parameters were compared using Kruskal-Wallis test according to the CYP3A and MDR1 genotype. We found that the values of AVC for CsA were significantly different among CYP3A5 and MDR1 exon 26 (C3435T) genotypes (P=0.037 and P=0.049). On the other hand, the AUC for FK506 was significantly different only among CYP3A5 genotypes (P=0.013). The results clearly demonstrate the effects of CYP3A5 and MDR1 exon 26 on Cys and FK506 disposition.

• The Korean Journal of Physiology and Pharmacology
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• 제19권2호
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• pp.99-104
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• 2015

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra- abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, $C_{max}$ was $11.151{\mu}g/mL$ at 5 min after the intravenous injection and $t_{1/2}$ was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.

• 대한예방한의학회지
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• 제17권1호
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• pp.77-88
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• 2013

Objectives : This study was aim to evaluate effects of pharmacodynamics and toxicity in combination therapy of donepezil with Gongjindan. Methods : After 10mg/kg of donepezil treatment, Gongjindan 100mg/kg was administered within 5 min. The plasma were collected at 30min before administration, 30min, 1, 2, 3, 4, 6, 8 and 24hrs after end of Gongjindan treatment, and plasma concentrations of donepezil were analyzed using LC-MS/MS methods. PK parameters of donepezil were analysis as compared with donepezil single administered rats. Results : Gongjindan markedly inhibited the absorption of donepezil regardless of sample time, from 30min to 8hrs after end of co-administration comparing with donepezil single treated rats. Especially the absorption of donepezil was significantly decreased at 2hrs after co-administration as compared with donepezil single treated rats, in the present study. Accordingly, the Cmax(-27.76%), $AUC_{0-t}$(-27.22%) and $AUC_{0-inf}$(-26.54%) of donepezil in co-administered rats were significantly decreased as compared with donepezil single treated rats, respectively. Conclusions : Based on the results of the present study, co-administration of Gongjindan decreases the oral bioavailability of donepezil by inhibiting the absorption. It is considered that the more detail pharmacokinetic studies should betested to conclude the effects of Gongjindan on the pharmacokinetics of donepezil, when they were co-administered, like the effects after co-administration with reasonable intervals considering the Tmax of donepezil and after repeated co-administrations.

• Archives of Pharmacal Research
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• 제28권10호
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• pp.1190-1195
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• 2005

The objective of this study was to develop an assay for mequitazine (MQZ) for the study of the bioavailability of the drug in human subjects. Using one mL of human plasma, the pH of the sample was adjusted and MQZ in the aqueous phase extracted with hexane; the organic layer was then evaporated to dryness, reconstituted and an aliquot introduced to a gas chromatograph/mass spectrometer (GC/MS) system with ion-trap detector. Inter- and intra-day precision of the assay were less than 15.1 and $17.7{\%}$, respectively; Inter- and intra-day accuracy were less than 8.91 and $18.6{\%}$, respectively. The limit of quantification for the current assay was set at 1 ng/mL. To determine whether the current assay is applicable in a pharmacokinetic study for MQZ in human, oral formulation containing 10 mg MQZ was administered to healthy male subjects and blood samples collected. The current assay was able to quantify MQZ levels in most of the samples. The maximum concentration ($C_{max}$ was 8.5 ng/mL, which was obtained at 10.1 h, with mean half-life of approximately 45.5 h. Under the current sampling protocol, the ratio of $AUC_{t{\rightarrow}last}$ to $AUC_{t{\rightarrow}{\infty}}$ was $934{\%}$, indicating that the blood collection time of 216 h is reasonable for MQZ. Therefore, these observations indicate that an assay for MQZ in human plasma is developed by using GC/MS with ion-trap detector and validated for the study of pharmacokinetics of single oral dose of 10 mg MQZ, and that the current study design for the bioavailability study is adequate for the drug.

• 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.

• 대한예방한의학회지
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• 제23권1호
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• pp.83-94
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• 2019

Objective : This study investigated the effects of concentrated and lyophilized blue honeysuckle powders (BH) on the pharmacokinetics (PK) of sorafenib were observed. Method : The blood was collected at 0.5 hr before single oral treatment of sorafenib (40 mg/kg) or sorafenib with BH (400, 200 and 100 mg/kg) mixed formulas administration, and 0.5, 1, 2, 3, 4, 6, 8 and 24 hrs after the end of single or mixed formula administration. Plasma concentrations of sorafenib were analyzed using LC-MS/MS methods. Tmax, Cmax, AUC, $t_{1/2}$ and $MRT_{inf}$ of sorafenib were analysis as compared with sorafenib single treatment. Results : Single oral administration of mixed formulas induced significant increases of plasma sorafenib concentrations from 0.5 hr after end of administration throughout all blood collected time points, as compared with sorafenib single formula treated rats, and significant decreases of sorafenib Tmax with increases of Cmax, $AUC_{0-t}$ and $AUC_{0-inf}$ were detected in sorafenib and BH 400 mg/kg mixed formulation treated rats as compared with sorafenib single formula treated rats, respectively. Inaddition, sorafenib and BH 200 or 100 mg/kg mixed formula treated rats also showed significant increases of sorafenib Cmax, $AUC_{0-t}$ and $AUC_{0-inf}$, respectively. Conclusions : According to these results, mixed formulation of BH with sorafenib increased the bioavailability of sorafenib through the increment of the absorptions.

• Tuberculosis and Respiratory Diseases
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• 제52권2호
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• pp.128-136
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• 2002

연구배경 : 다제내성 결핵 환자에서 fluoroquinolone계 약물이 빈번하게 처방되고 있음에도 불구하고, 이의 약동학적 특성에 대한 연구가 부족한 실정이다. 그러므로, 본 연구에서는 fluoroquinolone계 약물의 하나인 ofloxacin을 복용하고 있는 다제내성 결핵 환자에서의 ofloxacin의 약동학적 특성을 분석하였고, 아울러 ofloxacin의 약동학적 특성을 전신쇠약 상태와 연관지어 분석하였다. 방 법 : 300 mg b.i.d. 의 ofloxacin 용법을 포함하여 prothionamide, cycloserine, para-aminosalicylic acid, kanamycin 및 streptomycm 등의 2차 항결핵제제를 복용 중인 20명의 다제내성 결핵 환자를 대상으로 하였다. 전신쇠약 상태가 ofloxacin의 약동학에 미치는 영향을 평가하기 위하여 body mass indes (BMI)에 따라 환자를 두 군 (A 군 ; 18.5 $\leq$ BMI < 23, B군 : < 18.5)으로 나누어 두 군간의 ofloxacin의 항정상태 약동학적 특성을 비교분석하였다. 한 달 이상의 고정용법으로 항정상태에 이른 피험자에서 약동학 연구를 위하여 혈액을 경시적으로 13회 취하였고, 뇨 시료도 24 사간까지 취하였다. 혈장 및 뇨의 ofloxacin 농도를 HPLC를 이용하여 측정한 후 각각의 약동학적 분석을 시행하였다. 결 과 : Ofloxacin 의 AUC는 B군에서 $31.4{\pm}8.9{\mu}g/ml{\cdot}h$로 A군의 24.1+6.2 ${\mu}g/ml{\cdot}h$보다 유의하게 큰 것으로 나타났다(p<0.05). 항정상태에서 A군의 ofloxacin의 청소율 (Cl/F)은 $0.16{\pm}0.03$ L/h/kg로 산출되었고, B군에서는 $0.14{\pm}0.03$ L/h/kg로 나타났다. Ofloxacin의 반감기($t_{1/2}$)는 두 군간에 차이를 보이지 않았다(A군 : $5.3{\pm}0.8$시간, B군 $5.7{\pm}0.9$시간)으며 다른 약동학적 경수들도 두 군간의 유의한 차이를 보이지 않았다. 결 론 : 이상의 연구결과는 정상 피험자에 비하여 다제내성 결핵 환자에서 ofloxacin의 약동학적 특성이 유의하게 다르지 않음을 나타내고 있다. 한편, 만성 다제내성 결핵 환자의 전신쇠약 정도는 혈장 ofloxcaicn의 농도에 변화를 유발하는 것으로 기대된다.

• 제어로봇시스템학회:학술대회논문집
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• 제어로봇시스템학회 2004년도 ICCAS
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• pp.330-335
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• 2004

Phase specific models for cancer chemotherapy are described as optimal control problems. We review earlier results on scheduling optimal therapies when the controls represent the effectiveness of chemotherapeutic agents, or, equivalently, when the simplifying assumption is made that drugs act instantaneously. In this paper we discuss how to incorporate more realistic medical aspects which hitherto have been neglected in the models. They include pharmacokinetic equations (PK) which model the drug's plasma concentration and various pharmacodynamic models (PD) which describe the effect the concentrations have on cells. We also briefly discuss the important medical issue of drug resistance.

• Translational and Clinical Pharmacology
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• 제25권3호
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• pp.153-156
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• 2017

UI14SDF100CW is a chewable tablet of sildenafil citrate, which was developed to improve compliance through convenience of administration. The purpose of this study was to compare the pharmacokinetic (PK) properties of sildenafil citrate chewable tablets (UI14SDF100CW) and conventional sildenafil citrate film-coated tablets ($Viagra^{(R)}$, Pfizer). A randomized, open-label, single dose, two-treatment, two-period, two-way crossover study was conducted in 60 healthy male volunteers. In each period, the subjects received a single oral dose of UI14SDF100CW or $Viagra^{(R)}$ (both tablets contain 140.45 mg of sildenafil citrate, which is equivalent to 100 mg of sildenafil). Serial blood samples were collected up to 24 h post-dose for PK analysis. The plasma concentration of sildenafil was determined using a validated HPLC-MS/MS assay. PK parameters of sildenafil were calculated using non-compartmental methods. The plasma concentration-time profiles of sildenafil in both formulations were similar. For UI14SDF100CW, the $C_{max}$ and $AUC_{last}$ of sildenafil were $1068.69{\pm}458.25$ (mean${\pm}$standard deviation) mg/L and $3580.59{\pm}1680.29h{\cdot}mg/L$, and the corresponding values for $Viagra^{(R)}$ were $1146.84{\pm}501.70mg/L$ and $3406.35{\pm}1452.31h{\cdot}mg/L$, respectively. The geometric mean ratios (90% confidence intervals) of UI14SDF100CW to $Viagra^{(R)}$ for $C_{max}$ and $AUC_{last}$ were 0.933 (0.853-1.021) and 1.034 (0.969-1.108), respectively, which met the bioequivalence criteria of Korean regulatory agency. In conclusion, UI14SDF100CW and $Viagra^{(R)}$ showed similar PK properties. Therefore, UI14SDF100CW can be an alternative to sildenafil for the treatment of erectile dysfunction, providing better compliance.