The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old m...The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.展开更多
The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscibl...The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscible media that are in contact under conditions of constant phase volumes, at equilibrium. Its value is not affected by the total system solute mass and it only depends on the total system volume, the phase volumes and the affinity of the solute for the two phases in the system. Using this new concept of the apparent volume of distribution, we were able to demonstrate that under certain conditions compartment volumes in multi-compartment and multi-phasic pharmacokinetic models represent the actual physiological volumes of body fluids accessible by drugs. The classical pharmacokinetic models are now fully explained and can be used to provide accurate estimation of the pharmacokinetic parameters for hydrophilic drugs. In contrast, in the absence of tissue-plasma partition coefficients, lipophilic drugs that do not follow a one-compartment model are unlikely to be adequately described with classical multi-compartment pharmacokinetic models.展开更多
The present study was designed to determine the effects of Guanfu base A(GFA) on the late sodium current(INa.L),transient sodium current(INa.T),HERG current(IHERG),and Kv1.5 current(IKv1.5).The values of INa.L,INa.T,I...The present study was designed to determine the effects of Guanfu base A(GFA) on the late sodium current(INa.L),transient sodium current(INa.T),HERG current(IHERG),and Kv1.5 current(IKv1.5).The values of INa.L,INa.T,IHERG and IKv1.5 were recorded using the whole-cell patch clamp technique.Compared with other channels,GFA showed selective blocking activity in late sodium channel.It inhibited INa.L in a concentration-dependent manner with an IC50 of(1.57 ± 0.14) μmol·L-1,which was significantly lower than its IC50 values of(21.17 ± 4.51) μmol·L-1 for the INa.T.The inhibitory effect of GFA on INa,L was not affected by 200μmol·L-1 H2O2.It inhibited IHERG with an IC50 of(273 ± 34) μmol·L-1 and has slight blocking effect on IKv1.5,decreasing IKv1.5 by only 20.6% at 200 μmol·L-1.In summary,GFA inhibited INa.L selectively and remained similar inhibition in presence of reactive oxygen species..These findings may suggest a novel molecular mechanism for the potential clinical application of GFA in the treatment of cardiovascular disorders.展开更多
Background: The 2020 consensus guidelines recommend AUC guided dosing as the preferred monitoring method for vancomycin. AUC based dosing has shown to reduce incidence of acute kidney injury (AKI), utilize lower daily...Background: The 2020 consensus guidelines recommend AUC guided dosing as the preferred monitoring method for vancomycin. AUC based dosing has shown to reduce incidence of acute kidney injury (AKI), utilize lower daily doses in obese patients, and maintain efficacy. Several institutions have adjusted their protocols to utilize AUC guided dosing. However, there are limited studies comparing the clinical outcomes of AUC versus trough monitoring. Methods: This was a retrospective, observational, single centered study. The primary outcome was to evaluate the clinical success of AUC dosing versus trough based dosing of vancomycin for MRSA infections using a composite outcome of afebrile post treatment ( Results: Forty-seven patients were included in this study, 17 in the AUC group and 30 in the trough group. The primary composite outcome showed a significant benefit of AUC dosing (p = 0.04). The composite component culture clearance showed the largest improvement for the AUC group when compared with the trough group (p = 0.03). More patients achieved therapeutic target attainment and reached the target sooner (3 days versus 4 days, p = 0.2) in the AUC group. Over the study course, 94.1% of patients in the AUC group were considered therapeutic compared to 63.8% in the trough group (p = 0.03). Vancomycin levels were collected less frequently in the AUC group (3 versus 4, p = 0.2). Conclusion: The outcomes of this study may suggest AUC guided dosing as a beneficial alternative to trough based dosing. AUC based dosing may improve clinical success which can be further explored in larger prospective clinical trials.展开更多
Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic...Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.展开更多
The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dis...The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.展开更多
Novel human interferon alpha 2b (hIFNα2b) muteins were developed by substituting cysteine residue (C) at positions 2 and 99 with aspartic acid residues (D). The mutein forms were then studied for pharmacokinetic prof...Novel human interferon alpha 2b (hIFNα2b) muteins were developed by substituting cysteine residue (C) at positions 2 and 99 with aspartic acid residues (D). The mutein forms were then studied for pharmacokinetic profile. In addition, the influence of charge on the protein structure was tested in vivo for the biodistribution pattern. Codon substitutions were performed by Polymerase Chain Reaction (PCR)-based site-directed mutagenesis on a previously constructed synthetic hIFNα2b open reading frame (ORF) cloned in pET32b expression plasmid. The result of nucleotide sequencing analysis confirmed that all codons were replaced successfully without any additional mutation. Three mutant forms of hIFNα2b ORF were overexpressed in Escherichia coli BL21 (DE3) resulted in three muteins: hIFNα2b C2D, hIFNα2b C99D, hIFNα2b C2D C99D. To follow the kinetic and localization of the mutein interferon after intravenous administration, Tc99m was used to label the proteins. In particular of elimination half-life, it was shown that hIFNα2b C2D C99D > hIFNα2bC2D > hIFNα2bC99D > wild type. hIFNα2b C2D C99D mutein showed highest blood accumulation after 30 minutes administration. Taken together, the charge of hIFNα2b seems to be responsible for the fate of hIFNα2b in vivo.展开更多
文摘The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.
文摘The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscible media that are in contact under conditions of constant phase volumes, at equilibrium. Its value is not affected by the total system solute mass and it only depends on the total system volume, the phase volumes and the affinity of the solute for the two phases in the system. Using this new concept of the apparent volume of distribution, we were able to demonstrate that under certain conditions compartment volumes in multi-compartment and multi-phasic pharmacokinetic models represent the actual physiological volumes of body fluids accessible by drugs. The classical pharmacokinetic models are now fully explained and can be used to provide accurate estimation of the pharmacokinetic parameters for hydrophilic drugs. In contrast, in the absence of tissue-plasma partition coefficients, lipophilic drugs that do not follow a one-compartment model are unlikely to be adequately described with classical multi-compartment pharmacokinetic models.
基金supported by the Fundamental Research Funds for the Central Universities(No.JKZ2011007)the National "Key Program for New Drug Research Development"(No.2009 ZX09103-345)
文摘The present study was designed to determine the effects of Guanfu base A(GFA) on the late sodium current(INa.L),transient sodium current(INa.T),HERG current(IHERG),and Kv1.5 current(IKv1.5).The values of INa.L,INa.T,IHERG and IKv1.5 were recorded using the whole-cell patch clamp technique.Compared with other channels,GFA showed selective blocking activity in late sodium channel.It inhibited INa.L in a concentration-dependent manner with an IC50 of(1.57 ± 0.14) μmol·L-1,which was significantly lower than its IC50 values of(21.17 ± 4.51) μmol·L-1 for the INa.T.The inhibitory effect of GFA on INa,L was not affected by 200μmol·L-1 H2O2.It inhibited IHERG with an IC50 of(273 ± 34) μmol·L-1 and has slight blocking effect on IKv1.5,decreasing IKv1.5 by only 20.6% at 200 μmol·L-1.In summary,GFA inhibited INa.L selectively and remained similar inhibition in presence of reactive oxygen species..These findings may suggest a novel molecular mechanism for the potential clinical application of GFA in the treatment of cardiovascular disorders.
文摘Background: The 2020 consensus guidelines recommend AUC guided dosing as the preferred monitoring method for vancomycin. AUC based dosing has shown to reduce incidence of acute kidney injury (AKI), utilize lower daily doses in obese patients, and maintain efficacy. Several institutions have adjusted their protocols to utilize AUC guided dosing. However, there are limited studies comparing the clinical outcomes of AUC versus trough monitoring. Methods: This was a retrospective, observational, single centered study. The primary outcome was to evaluate the clinical success of AUC dosing versus trough based dosing of vancomycin for MRSA infections using a composite outcome of afebrile post treatment ( Results: Forty-seven patients were included in this study, 17 in the AUC group and 30 in the trough group. The primary composite outcome showed a significant benefit of AUC dosing (p = 0.04). The composite component culture clearance showed the largest improvement for the AUC group when compared with the trough group (p = 0.03). More patients achieved therapeutic target attainment and reached the target sooner (3 days versus 4 days, p = 0.2) in the AUC group. Over the study course, 94.1% of patients in the AUC group were considered therapeutic compared to 63.8% in the trough group (p = 0.03). Vancomycin levels were collected less frequently in the AUC group (3 versus 4, p = 0.2). Conclusion: The outcomes of this study may suggest AUC guided dosing as a beneficial alternative to trough based dosing. AUC based dosing may improve clinical success which can be further explored in larger prospective clinical trials.
基金supported by the National Natural Science Foundation of China (81473362)。
文摘Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.
基金the National Natural Science Foundation of China (No. 81173009)the Technology Bureau in Shenyang (No. ZCJJ2013402)the Project for New Century Excellent Talents of Ministry of Education (No. NCET-12-1015)
文摘The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.
文摘Novel human interferon alpha 2b (hIFNα2b) muteins were developed by substituting cysteine residue (C) at positions 2 and 99 with aspartic acid residues (D). The mutein forms were then studied for pharmacokinetic profile. In addition, the influence of charge on the protein structure was tested in vivo for the biodistribution pattern. Codon substitutions were performed by Polymerase Chain Reaction (PCR)-based site-directed mutagenesis on a previously constructed synthetic hIFNα2b open reading frame (ORF) cloned in pET32b expression plasmid. The result of nucleotide sequencing analysis confirmed that all codons were replaced successfully without any additional mutation. Three mutant forms of hIFNα2b ORF were overexpressed in Escherichia coli BL21 (DE3) resulted in three muteins: hIFNα2b C2D, hIFNα2b C99D, hIFNα2b C2D C99D. To follow the kinetic and localization of the mutein interferon after intravenous administration, Tc99m was used to label the proteins. In particular of elimination half-life, it was shown that hIFNα2b C2D C99D > hIFNα2bC2D > hIFNα2bC99D > wild type. hIFNα2b C2D C99D mutein showed highest blood accumulation after 30 minutes administration. Taken together, the charge of hIFNα2b seems to be responsible for the fate of hIFNα2b in vivo.
