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

• Bulletin of the Korean Chemical Society
• /
• 제33권4호
• /
• pp.1123-1127
• /
• 2012

P-gp (P-glycoprotein) is a member of the ATP binding cassette (ABC) family of transporters. It transports many kinds of anticancer drugs out of the cell. It plays a major role as a cause of multidrug resistance (MDR). MDR function may be a cause of the failure of chemotherapy in cancer and influence pharmacokinetic properties of many drugs. Hence classification of candidate drugs as substrates or nonsubstrate of the P-gp is important in drug development. Therefore to identify whether a compound is a P-gp substrate or not, in silico method is promising. Recursive Partitioning (RP) method was explored for prediction of P-gp substrate. A set of 261 compounds, including 146 substrates and 115 nonsubstrates of P-gp, was used to training and validation. Using molecular descriptors that we can interpret their own meaning, we have established two models for prediction of P-gp substrates. In the first model, we chose only 6 descriptors which have simple physical meaning. In the training set, the overall predictability of our model is 78.95%. In case of test set, overall predictability is 69.23%. Second model with 2D and 3D descriptors shows a little better predictability (overall predictability of training set is 79.29%, test set is 79.37%), the second model with 2D and 3D descriptors shows better discriminating power than first model with only 2D descriptors. This approach will be used to reduce the number of compounds required to be run in the P-gp efflux assay.

• The Korean Journal of Physiology and Pharmacology
• /
• 제28권2호
• /
• pp.121-127
• /
• 2024

Vancomycin is a frequently used antibiotic in intensive care units, and the patient's renal clearance affects the pharmacokinetic characteristics of vancomycin. Several advantages have been reported for vancomycin continuous intravenous infusion, but studies on continuous dosing regimens based on patients' renal clearance are insufficient. The aim of this study was to develop a vancomycin serum concentration prediction model by factoring in a patient's renal clearance. Children admitted to our institution between July 1, 2021, and July 31, 2022 with records of continuous infusion of vancomycin were included in the study. Sex, age, height, weight, vancomycin dose by weight, interval from the start of vancomycin administration to the time of therapeutic drug monitoring sampling, and vancomycin serum concentrations were analyzed with the linear regression analysis of the mixed effect model. Univariable regression analysis was performed using the vancomycin serum concentration as a dependent variable. It showed that vancomycin dose (p < 0.001) and serum creatinine (p = 0.007) were factors that had the most impact on vancomycin serum concentration. Vancomycin serum concentration was affected by vancomycin dose (p < 0.001) and serum creatinine (p = 0.001) with statistical significance, and a multivariable regression model was obtained as follows: Vancomycin serum concentration (mg/l) = -1.296 + 0.281 × vancomycin dose (mg/kg) + 20.458 × serum creatinine (mg/dl) (adjusted coefficient of determination, R² = 0.66). This prediction model is expected to contribute to establishing an optimal continuous infusion regimen for vancomycin.

• 한국임상약학회지
• /
• 제21권2호
• /
• pp.145-155
• /
• 2011

The objective of this study was to determine whether any pretreatment parameters were associated with pharmacological effect or toxicity parameters after vincristine administration and to describe a mathematical model, which explains the interpatient pharmacodynamic variability. The relationship between patient characteristics and vincristine dose and hematological toxicity were evaluated. 68 pediatric and adolescence patients and 107 adults with acute lymphoblastic leukemia were treated with vincristine $1.5mg/m^2/day$ IV and other anticancer drugs as scheduled. Complete blood counts and other blood test results were obtained. The input variables were age, gender, weight, lean body weight (LBW), height, body surface area, vincristine dose and total vincristine dose. The outcome measures were nadir values (white blood cells, absolute neutrophil counts, hemoglobin, and platelets); the absolute decrease, relative decrease, and survival fraction of blood cells. Polynomial regression analysis was carried out to determine the other significant covariates. The variability of $WBC_{nadir}$ was modeled with good precision and accuracy with a two-covariate model. This model should be validated and improved on with further clinical data. We believe that such pharmacodynamic modeling should be explored further to determine its performance and clinical relevance compared with modeling using pharmacokinetic parameter.

• Archives of Pharmacal Research
• /
• 제21권5호
• /
• pp.503-507
• /
• 1998

Percutaneous absorption and model membrane variations of melationin (MT) in aqueous-based propylene glycol and $2-hydroxypropyl-{\beta}-cyclodextrin $vehicles were investigatted. the excised hairless mouse skin (HMS) and two synthetic ethylene vinyl acetate (EVA) and microporous polyethylene (MPE) were selected as a model membrane. the solubility of MT was determined by phase equilibrium study. the vertical $Franz{\circledR}$ type cell was used for diffusion study. The concentration of MT was determined using reverse phse HPLC system. The MT solubility was the highest in a mixture of PG and $2-HP{\beta}CD$. The percutaneous absorption of MT through excised HMS increased as the solubility increased. However, the permeability coefficient decreased and then slightly increased in mixture of PG and $2-HP{\beta}CD$. On the other hand, both flux and permeability coefficient through EVA membrane decreased as the solubility increased. No MT was detected over 12 h after starting diffusion through MPE membrane. The flux of MT was dependent on the type of membrane selected. Flux of MT was greatest in excised HMS followed by EBA and MPE membrane. Flux of MT through EVA membrane was 5-20 times lower when compared to excised HMS. Interestingly, volumes of donor phase when MPE membrane was used, significantly increased during the study period. the HMS might be applicable to expect plasma concentration of MT in human subjects based on flux and pharmacokinetic parameters as studied previously. the current studies may be applied to deliver MT transdermally using aqueous-based vehicles and to fabricate MT dosage forms.

• The Korean Journal of Physiology and Pharmacology
• /
• 제22권3호
• /
• pp.321-329
• /
• 2018

It was recently reported that the $C_{max}$ and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin $C_{maxI}/C_{max}$ and $AUC_I/AUC$ (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the $T_{max}$ changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report ($C_{maxI}/C_{max}$: 2.01, $AUC_I/AUC$:1.18, $T_{max}:5h{\rightarrow}0.75h$). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin $C_{maxI}/C_{max}$ and $AUC_I/AUC$ (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the $CL_{int,BCRP,intestine}$ of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction).

• Molecules and Cells
• /
• 제39권5호
• /
• pp.389-394
• /
• 2016

Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.

• KSBB Journal
• /
• 제26권3호
• /
• pp.217-222
• /
• 2011

Itraconazole is a triazole antifungal agent to inhibit most fungal pathogens. To improve the oral absorption and dissolution of poorly water-soluble itraconazole, microsponge system composed of $Eudragit^{(R)}$ E100 and polyvinyl alcohol(PVA) formulated by quasi-emulsion solvent diffusion method, and its physicochemical properties and pharmacokinetic parameters of itraconazole were studied. The microsponge of itraconazole were discrete free flowing micro sized particles with perforated orange peel like morphology as visualized by scanning electron microscope (SEM). Results showed that the drug loading efficiency, production yield, and particle size of itraconazole microsponge were affected by drug to polymer ratio, the volume of internal phase containing methylene chloride, stirring rate and the concentration of PVA used. Also, the results showed that the dissolution rate of itraconazole from the microsponges was affected by drug to polymer ratio. In other words, the release rate of itraconazole from microsponges was increased from at least 27.43% to 64.72% after 2 h. The kinetics of dissolution mechanism showed that the dissolution data followed Korsmeyer-Peppas model. Therefore, these results suggest that microsponge system can be useful for the oral delivery of itraconazole by manipulating the release profile.

• Journal of Applied Biological Chemistry
• /
• 제58권4호
• /
• pp.363-368
• /
• 2015

The pharmacokinetics of florfenicol were studied in healthy and vibriosis-infected large yellow croaker (Pseudosciaena crocea) following administration of a single oral dose of $20mg{\cdot}kg^{-1}$ at $25{\pm}2^{\circ}C$. After oral administration, florfenicol levels in tissues (liver, kidney, muscle, serum, and skin) were analyzed using high-performance liquid chromatography. A two-compartment open model was used to describe the pharmacokinetics of florfenicol following oral administration. Compared to the healthy group, the absorption rate of vibriosis-infected fish significantly decreased, peak-time ($T_{max}$) delayed, maximum concentration ($C_{max}$) declined, total body clearance decreased, the elimination half-life ($T_{1/2{\beta}}$) was extended, and the area under the curve increased. These results indicate that a $20mg{\cdot}kg^{-1}$ oral dose of florfenicol administered once daily continuously for 4 or 5 days can be used for the treatment of Vibrio alginolyticus infection in large yellow croaker (Pseudosciaena crocea).

• Environmental Analysis Health and Toxicology
• /
• 제12권3_4호
• /
• pp.43-54
• /
• 1997

Species, doses and routes extrapolation can be sucessfully carried out by using a physiologically-based pharmacokinetic (PBPK) approach. And PBPK approach to assess risk of hazardous chemicals is reasonable whatever the exposure scenarios are happened. Both partitioning coefficients of chemical between tissue and blood and enzymatic metabolic rate constants are key parameters to build up the PBPK model. In this study, we tried to estimate in vitro metabolic rate constants using a special apparatus instead to measure the in vivo constants which are used to PBPK simulation since the in vitro tests are less expensive and more convenient than in vivo tests. For the purpose, we designed and tested the new system to measure continuously the headspace concentration of VOC. The newly designed system is composed with a diffusion chamber which generates gaseous substrate, a reaction vessel with a recirculating pump to establish a closed system, an autbmatic sampler from a gas phase, a gas chromatography to analyze the headspace. In addition, a cold water condenser is attached between the reaction vessel and pump to reduce the content of gaseous moisture which interferes with chemical analysis. To validate the newly developed methodology, in vitro metabolic rate constants of trichloroethylene (TCE) as a prototype VOC were estimated by simulating observed results with an ACSL program. The simulated results are consistent to those estimated by the other research groups. This finding suggests that our newly designed closed system may be a useful apparatus to estimate in vitro metabolic rate constants for VOC.