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11.
Summary Blood flow rate-limited physiological pharmacokinetic models have been used to examine the relationship between apparent volume of distribution and clearance or, more specifically between drug binding in blood, eliminating regions or noneliminating regions and clearance. The influence of binding on drug elimination depends on the driving force concentration in the eliminating region. In most instances this is likely to be free drug concentration in the region. Under these conditions, the results indicate that apparent volume of distribution and drug clearance from the blood should be treated as independent pharmacokinetic variables. Volume of distribution per se has no effect on clearance or on average steady-state blood levels. Drug binding in nonvascular regions (i. e. tissue binding) seems to be of limited importance except as a determinant of half-life. Although changes in tissue binding will affect partition coefficient and apparent volume of distribution, such changes will have no effect on average steady-state blood levels of either total or free drug. 相似文献
12.
Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding II. Physiological significance 总被引:2,自引:0,他引:2
Guidelines presented previously for the analysis of plasma concentration versus time data for a drug exhibiting concentration-dependent plasma protein binding were successfully applied to the distributional parameters of a new cephalosporin, ceftriaxone. This approach provided several striking observations when the pharmacokinetics of ceftriaxone in a healthy and uremic population were re-examined. First, the parameter -fp converted the apparent dose-dependent distributional terms of ceftriaxone into a function of the concentration-dependent plasma protein binding. Second, a strong correlation between the term VUSS and the reciprocal of -fp was established within each of the two populations. While this -fp term accounted for the variability within the respective populations due to ceftriaxone-albumin binding differences, it did not account for all of the distributional differences between the two populations. The present analysis revealed that the altered physiologic state of uremia (larger plasma volumes and interstitial to intravascular albumin ratios), in addition to differences in plasma protein binding, dictated the distribution of ceftriaxone in healthy and uremic subjects. Furthermore, the binding-disposition model which accounts for the presence of plasma proteins outside the vascular space, was established to be appropriate in describing the distribution of ceftriaxone. 相似文献
13.
Summary A pharmacokinetic model that incorporates linear binding of drug to plasma proteins and tissue indicates the same relationship between apparent volume of distribution and drug binding as that proposed by Gillette (1971) based on a simple distribution model. Apparent volume of distribution (V) is directly proportional to free fraction of drug in plasma (fp) and indirectly proportional to free fraction of drug in tissue (fT). In the case of a constant fT, a plot of V versus fp will be linear with an intercept equal to plasma volume (Vp). If fT changes with fp, an apparently linear plot may result but the intercept will exceed Vp. An approach to the calculation of fT, a composite binding parameter, is presented and illustrated by comparing the tissue binding of tolbutamide in patients during acute viral hepatitis and upon recovery.Supported in part by Grant GM-20852 from the National Institutes of Health. 相似文献
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A recently developed pharmacokinetic model of the insulin-glucose system has been used to investigate the contribution of insulin-induced suppression of endogenous glucose production (EGP) to the hypoglycemic effect of insulin in the treatment of diabetic ketoacidosis and to determine the influence of the initial degree of hyperglycemia on the course of insulin treatment. Simulations of the time course of glucose concentration in the plasma following low-dose insulin therapy indicate that the hypoglycemic action of insulin is largely due to insulin-dependent glucose utilization and that suppression of EGP, if it occurs at all, contributes little to the overall effect. Nevertheless, a particularly useful characteristic of the pharmacokinetic model of the insulin-glucose system that assumes little or no suppression of EGP is its ability to predict glucose rebound when insulin has been effectively depleted. Other simulations reveal that the initial degree of hyperglycemia has little influence on the clinical outcome of low-dose insulin treatment of diabetic ketoacidosis. According to the simulation, 0.1 (U/kg)/hr intravenous infusion of insulin will produce satisfactory control of plasma glucose concentrations within 5–8 hr, assuming initial glucose concentrations ranging from 500 to 1500 mg/dl. 相似文献
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Effect of mode of administration on drug distribution in a two-compartment open system 总被引:2,自引:0,他引:2
M Gibaldi 《Journal of pharmaceutical sciences》1969,58(3):327-331
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Patrick J. McNamara John T. Slattery Milo Gibaldi Gerhard Levy 《Journal of pharmacokinetics and pharmacodynamics》1979,7(4):397-405
The purpose of this investigation was to study, by digital computer simulation, the accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free fraction with increasing drug concentration) binding to plasma proteins. It was assumed that elimination rate is proportional to free drug concentration in plasma and that there occurs instantaneous equilibration of drug between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentrationtime curves which may be misinterpreted as being representative of a linear and biexponential-system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constantrate infusion: (a) the time required to reach steady state may be overestimated, and (b) the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relationship between infusion rate and steadystate concentration. This relationship is linear when plasma protein binding is linear. Steadystate concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent. 相似文献
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