title: Interpretation and utilization of effect and concentration data collected in an in vivo pharmacokinetic and in vitro pharmacodynamic study.
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 (MA); the extent of hysteresis will depend upon the pharmacokinetics and relative "potency" of C and MA. If a nonspecific assay is used, plots of E vs C may actually relate to E vs total agonist (C + MA), and unusual hysteresis may be observed, e.g., clockwise hysteresis when C is more "potent" than MA. Here, we simulate data for three models of relative C and MA pharmacokinetics. The E vs C and E vs MA data are simulated for both linear and noncompetitive agonist Emax models. When C and MA are equally potent, hysteresis will not be observed in a plot of E vs C + MA. However, when C and MA are of differing "potencies," hysteresis will be observed (the direction of hysteresis is dependent on the relative potency of C and MA). By appropriately "weighting" a respective agonist (C or MA), hysteresis will "collapse" and the relative potencies of C and MA can be estimated.
authors.affiliation: Department of Pharmacokinetics, ALZA Corporation, Palo Alto, California 94304.
authors.forename: S K
authors.initials: SK
authors.lastname: Gupta
authors.forename: S S
authors.initials: SS
authors.lastname: Hwang
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: M
authors.initials: M
authors.lastname: Gumbleton
mesh_terms: D008962:Models, Theoretical; D010599:Pharmacokinetics; D010600:Pharmacology