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
Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral ro...Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.展开更多
Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance...Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.展开更多
The first biphasic open one-compartment pharmacokinetic model is described. Its analytical solutions to drug concentration were developed from parameters of an open two-compartment pharmacokinetic model. The model is ...The first biphasic open one-compartment pharmacokinetic model is described. Its analytical solutions to drug concentration were developed from parameters of an open two-compartment pharmacokinetic model. The model is used to explain the unusually large compartment volumes and apparent volumes of distribution of lipophilic drugs, as well as to identify which of the pharmacokinetic parameters of the classical compartment models are biologically relevant.展开更多
目的提供一种药物在中心室平均滞留时间(mean residence time in central compartment,MRTc)的计算方法。方法将药物浓度-时间曲线转换为药物分子数量-时间曲线,对此曲线下面积进行积分,得药物分子在中心室滞留的总时间,除以药物分子总...目的提供一种药物在中心室平均滞留时间(mean residence time in central compartment,MRTc)的计算方法。方法将药物浓度-时间曲线转换为药物分子数量-时间曲线,对此曲线下面积进行积分,得药物分子在中心室滞留的总时间,除以药物分子总数可得中心室平均滞留时间。通过对仿真数据中心室平均滞留时间的计算,对算法进行评价。结果最终的算法为MRTc=(AUC·V)/(F·Dose),该算法对血管内、外给药的线性和非线性动力学数据均有可靠的计算结果。结论 (AUC·Vc/F·Dose)可用于计算药物的中心室平均滞留时间,与药物在整个机体的平均滞留时间(mean residence time,MRT)的计算方法,MRT=(AUMC/AUC)配合使用有助于更好的阐述药物的体内行为。展开更多
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.
文摘Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.
文摘Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.
文摘The first biphasic open one-compartment pharmacokinetic model is described. Its analytical solutions to drug concentration were developed from parameters of an open two-compartment pharmacokinetic model. The model is used to explain the unusually large compartment volumes and apparent volumes of distribution of lipophilic drugs, as well as to identify which of the pharmacokinetic parameters of the classical compartment models are biologically relevant.
文摘目的提供一种药物在中心室平均滞留时间(mean residence time in central compartment,MRTc)的计算方法。方法将药物浓度-时间曲线转换为药物分子数量-时间曲线,对此曲线下面积进行积分,得药物分子在中心室滞留的总时间,除以药物分子总数可得中心室平均滞留时间。通过对仿真数据中心室平均滞留时间的计算,对算法进行评价。结果最终的算法为MRTc=(AUC·V)/(F·Dose),该算法对血管内、外给药的线性和非线性动力学数据均有可靠的计算结果。结论 (AUC·Vc/F·Dose)可用于计算药物的中心室平均滞留时间,与药物在整个机体的平均滞留时间(mean residence time,MRT)的计算方法,MRT=(AUMC/AUC)配合使用有助于更好的阐述药物的体内行为。
