EVALUATION OF THE ALPHA(2)-ADRENOCEPTOR BLOCKING PROPERTIES OF BUSPIRONE AND IPSAPIRONE IN HEALTHY-SUBJECTS - RELATIONSHIP WITH THE PLASMA-CONCENTRATION OF THE COMMON METABOLITE 1-(2-PYRIMIDINYL)-PIPERAZINE

1 Because the 5-HT1A agonist anxiolytic azapirones have a common alpha(2)-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (1PP). we measured central and peripheral az-adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day(-1) for il days and 10 mg on day 5), ipsapirone (15 mg day(-1) for 4 days and 5 mg on day 5) or placebo. 2 Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4-dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C-peptide concentrations, Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3 The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4 Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma 1PP concentration which was higher on buspirone than on ipsapirone (2.76 mu g l(-1), 95% CI:1.3-4.22 vs 0.65 mu g l(-1), 95% CI: 0.32-0.98, P = 0.006). 5 Mean AUC of the 1PP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC 1PP ratio was 6.45 and the AUC buspirone/AUC 1PP ratio was 0.076. 6 The formation of the common metabolite 1PP is greater with buspirone than with ipsapirone. Buspirone but not ipsapirone (both given in therapeutically equivalent doses) exerted a psychostimulatory effect and this could be attributed to the higher plasma 1PP concentrations found with buspirone. 7 A clearcut antagonism of clonidine actions by 1PP could not be demonstrated probably because the ratio of the exogeneous alpha(2)-adrenoceptor agonist (clonidine) to the endogenously formed alpha(2)-adrenoceptor antagonist (1PP) could not be controlled.