Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models

AbstractDrug –target binding kinetics (as determined by association and dissociation rate constants,kon andkoff) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug –target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment–target binding kinetics (EC–TB) model were tested on either plasma (ECPL, TBPL and EC –TBPL) or brain extracellular fluid (ECF) (ECECF, TBECF and EC –TBECF) morphine concentrations and EEG amplitude in rats. It was also analyzed when a significant shift in the time to maximal target occupancy (TmaxTO) with increasing dose, the discriminating feature between the TB and EC model, occurs in the TB model. All TB models assumed a linear relationship between target occupancy and drug effect on the EEG amplitude. All three model types performed similarly in describing the morphine pharmacodynamics data, although the EC model provided the best statistical result. The analysis of the shift in TmaxTO ( ∆TmaxTO) as a result of increasing dose revealed that ∆TmaxTO is decreasing towards zero if thekoff is much smaller than the elimination rate constant or if the target concentration is larger than the initial morphine concentration. The results for the morphin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research