Structural effects in drug distribution: comparative pharmacokinetics of apomorphine analogues

Abstract

Abstract A two compartment open model, modified to include brain as a third compartment, was found to describe the pharmacokinetics of three aporphines in mice. Data include whole animal analysis, brain analysis and evaluation of stereotypical gnawing behaviour. The relative potencies of the derivatives, based upon brain content, were found to be apomorphine = 1, norapomorphine = 0·06 and N-n-propylnorapomorphine = 0·39. The potency of the N-n-propyl analogue is less than that previously reported on an intraperitoneal (i.p.) dosage basis (1·14). The ability to distribute into the brain, based on the entire time course for drug in that compartment, appears to be N-n-propylnorapomorphine >apomorphine >norapomorphine. The values for t 1/2 in mice are 29 min for the N-n-propyl derivative, 20 min for norapomorphine and 47 min for apomorphine which was previously reported to be 8·5 min based upon the inappropriate assumption of a one compartment model. The successful pharmacokinetic analysis was combined with the evaluation of structural effects on drug distribution and its resultant influence on pharmacokinetic response for the three closely related derivatives to demonstrate the applicability of the previously described whole animal pharmacokinetic treatment (Notari, Burkman & Van Tyle, 1974).