ISSN:
1573-8744
Keywords:
dynamics of drug distribution
;
curve moments
;
residence time distribution
;
circulation time distribution
;
variance
;
skewness
;
drug disposition curve
;
mixing curve
;
non-compartmental analysis
;
recirculation model
;
noneliminating and eliminating system
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Conventionally, the dynamics of distribution in the body is evaluated by the so-called distribution half-life (e.g., t 1/2,α but then the mean time of the distribution process is underestimated due tothe influence of elimination. By contrast, information about the dynamics of distribution contained in drug disposition curves can be extracted by the second and third curve moments, parameters that are related to the variance (VDRT)and skewness (SDRT)of residence time distributions; whereas the equilibrium state characterized by the volume of distribution (Vss), isdetermined by the mean residence time (MDRT)or the first curve moment. The approach represents a general noncompartmental analysis that is independent of a detailed structural model or a particular disposition function. Two parameters are introduced to characterize the dynamics of drug distribution: (i)the degree of departure of the system from “well-mixed” behavior of instantaneous distribution equilibrium (related to VDRT)and (ii)the mean time until equilibration is achieved (mean equilibration time, MEQT),which additionally depends on SDRT.Both parameters are quantitative measures of the dynamics of distribution and display explicit physical significance in terms of distribution within the corresponding noneliminating system. It is further shown that the so-called “distribution phase” in biexponential disposition curves is related to a monoexponential mixing curve of its corresponding noneliminating system with an equilibration or mixing half-time, t 1/2,M =t 1/2,α (Vβ/V ss * ), where V ss * denotes the distribution volume of the noneliminating system. The results are applied to mixing and disposition curves measured for acetaminophen in liver-ligated and intact rats, respectively.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF01062527
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