Peripheral pharmacokinetics of apomorphine in humans

Abstract

Apomorphine, a potent dopamine agonist, has been used in acute and chronic studies of parkinsonism and other neurological disorders. To define its peripheral pharmacokinetics, we administered apomorphine by subcutaneous injection, by subcutaneous infusion, and by intravenous infusion to 15 patients with parkinsonism and measured plasma apomorphine levels by high-performance liquid chromatography with electrochemical detection. The peak drug levels and area under the curve were closely correlated with the dose administered; time to peak was brief and was independent of dose. The variation in absorption was high between subjects but low within individual subjects. In 11 of 15 subjects, the disappearance of drug could be described by a two-compartment model, with a distribution half-life of 5 minutes and an elimination half-life of 33 minutes. The drug absorption, volume of distribution, plasma clearance, and half-lives were similar for subcutaneous injection, subcutaneous infusion, and intravenous infusion. We conclude that apomorphine is rapidly and completely absorbed from subcutaneous tissue, correlating with the rapid onset of clinical effects, and that the brief duration of clinical action of the drug is explained by its rapid clearance.

A study of tolerance to apomorphine

“…unlikely explanation for our findings since the available pharmacokinetic studies with apomorphine show that withinsubject variation in absorption after repeated subcutaneous administration is low (Gancher et al, 1989;Grandas & Obeso, 1989;Montastruc et al, 1991). Although the present experiments were not designed to investigate cellular mechanisms, one could hypothesize (as suggested by Costentin et al, 1975;) that tolerance to repeated injections of apomorphine involves D2 dopamine receptor desensitization.…”

The Effect of Apomorphine, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) and Placebo on Smooth Pursuit Gain and Corrective Saccades in Normal Subjects

“…The reduc tion was marked and rapid (from .895 to 0.771 in 30 min for slow-target-gain and from 0.844 to 0.751 for fast target-gain). As mentioned previously, the pharma cokinetic data, as well as studies of motor effects in Par kinson patients, indicate that apomorphine can act within 10 min (Gancher et al 1989;Truelle et al 1975). …”

“…The pharmacokinetics of apomorphine (bolus SC in jection) in humans have been described by Gancher et al (1989). According to them, apomorphine is rapidly absorbed following subcutaneous injection, with peak plasma concentrations occurring 3 min following ad ministration.…”

“…Concentrations are up to eight times higher in brain than plasma. Antiparkinsonian effects of apomorphine are observed within 7 min and last for up to 1 hr fol lowing injection (Gancher et al 1989;Truelle et al 1975).…”

Subcutaneous apomorphine increases regional cerebral blood flow in parkinsonian patients via peripheral mechanisms.

“…As no clinical motor change was supposed to occur, the moment of the second rCBF measurement was arbitrarily chosen 10 min after the s.c. injection of apomorphine. According to published data, this time was believed to correspond to the tmax of the drug (Gancher et al, 1989).…”