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 alpha 2‐adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day‐1 for 4 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 micrograms l‐1, 95% CI:1.3‐4.22 vs 0.65 microgram 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.(ABSTRACT TRUNCATED AT 250 WORDS)