ISSN:
1573-904X
Keywords:
in vitro
;
pharmacokinetics-pharmacodynamics
;
hysteresis
;
metabolite(s)
;
nonspecific analytical assay
;
drug discovery/ development
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The effect (E) of some drugs may be monitored in vitro using the plasma drug concentration (C) following the in vivo dosing of drug. When using a specific analytical assay, counterclockwise hysteresis in the E vs C relationship can be explained only by the presence of an agonistic metabolite (M A); the extent of hysteresis will depend upon the pharmacokinetics and relative "potency” of C and M A. If a nonspecific assay is used, plots of E vs C may actually relate to E vs total agonist (C + M A), and unusual hysteresis may be observed, e.g., clockwise hysteresis when C is more "potent” than M A. Here, we simulate data for three models of relative C and M A pharmacokinetics. The E vs C and E vs M A data are simulated for both linear and noncompetitive agonist E max models. When C and M A are equally potent, hysteresis will not be observed in a plot of E vs C + M A. However, when C and M A are of differing "potencies,” hysteresis will be observed (the direction of hysteresis is dependent on the relative potency of C and M A). By appropriately "weighting” a respective agonist (C or M A), hysteresis will "collapse” and the relative potencies of C and M A can be estimated.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1018969429535
