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)
Berlin
I
I
Département de Pharmacologie Clinique, Hôpital Pitié-Salpêtrière, Paris, France.
Chalon
S
S
Payan
C
C
Schöllnhammer
G
G
Cesselin
F
F
Varoquaux
O
O
Puech
A J
AJ
D000317:Adrenergic alpha-Antagonists / Q000097:blood*; D000328:Adult; D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002065:Buspirone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002096:C-Peptide / Q000097:blood; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013006:Growth Hormone / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D014151:Anti-Anxiety Agents; D002096:C-Peptide; D007328:Insulin; D011743:Pyrimidines; D012702:Serotonin Antagonists; D008734:Methoxyhydroxyphenylglycol; C043077:ipsapirone; D013006:Growth Hormone; C037921:1-(2-pyrimidinyl)piperazine; D003000:Clonidine; D002065:Buspirone; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine