In-vitro and in-vivo metabolism of the presynaptic dopamine agonist 3-PPP to a catecholic analogue in rats

The dopamine agonist 3-PPP and its enantiomers are hydroxylated in-vitro by rat liver microsomes to the catecholamine 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine (4-OH-3-PPP) with Km and Vmax values of about 1 microM and 2 nmol (mg protein)-1 min-1 respectively. As the catecholamine formed appears to be a good substrate for catechol-O-methyltransferase, in-vivo catecholamine formation in rats from 3-PPP was only detectable after inhibition of COMT by tropolone. The resulting brain levels of 4-OH-3-PPP, as measured by HPLC with electrochemical detection 45 min after administration, were about 350 pmol g-1 after i.p., and about 100 pmol g-1 after s.c. injection of 45 mumol kg-1 3-PPP, with no significant difference between racemic, ( + ) or (-) 3-PPP. It was estimated that these catecholamine levels represent about 1-5% of the 3-PPP levels after i.p., and about 0.2-0.5% after s.c. administration of 3-PPP. The relevance of this metabolic conversion of 3-PPP for its pharmacological profile is discussed