Isapirone-HCl (5 mg) was administered orally, rectally and locally, by a remote control drug delivery device (HF-capsule) into different segments of the gastrointestinal tract, to four young healthy male adults. The relative systemic bioavailability of the drug from the colon and rectum was 2-3-fold greater than that from the upper gastrointestinal tract. This supports a rationale for a prolonged-release formulation.

1 Because the 5-HTlA agonist anxiolytic azapirones have a common a2-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (IPP), we measured central and peripheral a2-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-'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 lPP concentration which was higher on buspirone than on ipsapirone (2.76 ,ug 1-1, 95% CI:1.3-4.22 vs 0.65 ,ug I1-, 95% CI: 0.32-0.98, P = 0.006). 5 Mean AUC of the IPP 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 IPP ratio was 6.45 and the AUC buspirone/AUC lPP ratio was 0.076. 6 The formation of the common metabolite IPP 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 lPP concentrations found with buspirone. 7 A clearcut antagonism of clonidine actions by IPP could not be demonstrated probably because the ratio of the exogeneous a2-adrenoceptor agonist (clonidine) to the endogenously formed a2-adrenoceptor antagonist (1 PP) could not be controlled.

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Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g t1/2 beta values were 5.5 and 4.7 h, respectively, mean-g tmax data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g Cmax maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag, tmax, and Cmax. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite "reduced benperidol" were found to be very low.

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