1-(2-Pyrimidinyl)-Piperazine as Active Metabolite of Buspirone in Man and Rat

Caccia, Silvio; Conti, I.; Viganò, Gianluigi; Garattini, Silvio

doi:10.1159/000138199

Cited by 112 publications

(55 citation statements)

References 7 publications

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“…In the present study, it was estimated on the basis of the two-compartment model with metabolite formation that at least 26% of the administered dose of buspirone is metabolized into 1-PP. Again, this appears to be consistent with findings of Caccia et al (1986) and Jajoo et al (1989aJajoo et al ( , 1989b who showed that 25% of the administered dose is excreted into urine as 1-PP. Overall the pharmacokinetics of both buspirone and 1-PP could be characterized successfully using the metabolite model.…”

Section: Discussionsupporting

confidence: 91%

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Zuideveld

Rusiç-Pavletiç

Maas

et al. 2002

J Pharmacol Exp Ther

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The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokineticpharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with setpoint control. Both buspirone and 1-PP behaved as partial agonists relative to R-(ϩ)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine 1A agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.Buspirone is a selective 5-HT 1A agonist that is used clinically as an anxiolytic drug (for reviews on its pharmacological properties, see New, 1990 andFulton and Brogdon, 1997). In vivo buspirone is metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP), which also possesses affinity to the 5-HT 1A receptor. This metabolite could therefore contribute to the effect of buspirone (Bianchi et al., 1988;Manahan-Vaughan et al., 1995;Cao and Rodgers, 1997). At present there is limited quantitative information on the magnitude of this effect. In theory the contribution of the metabolite to the effect is determined by the relative concentrations of buspirone and 1-PP, their relative in vivo potency and intrinsic activity, and the nature of the pharmacodynamic interaction between the two.Recently we have developed a physiological pharmacokinetic-pharmacodynamic (PK-PD) model to quantitatively characterize the pharmacodynamics of 5-HT 1A receptor agonists in vivo using the hypothermic effect as a pharmacodynamic endpoint (Zuideveld et al., 2001(Zuideveld et al., , 2002a. The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al., 1993;Cryan et al., 1999). It has been shown that the PK-PD model allows for the estimation of the in vivo potency and intrinsic activity of a wide array of different 5-HT 1A agonists such as R-8- -100,635), and Flesinoxan (Zuideveld et al., 2001, 2002a, 2002b. In the present investigation we apply this model to determine the relative in vivo po...

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Section: Discussionsupporting

confidence: 91%

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Zuideveld

Rusiç-Pavletiç

Maas

et al. 2002

J Pharmacol Exp Ther

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show abstract

“…1-PP is an active metabolite and it was reported that 1-PP may be involved in the anxiolytic effects of buspirone (17,20). Buspirone is rapidly metabolized to 1PP, and 1-PP levels in the brain and plasma are 10-and 15-fold higher than those of buspirone 15 min after the injection of buspirone (21).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Serotonergic Anxiolytic Buspirone on Plasma Glucose and Glucose-Induced Hyperglycemia in Mice

Sugimoto¹,

Takashima²,

Noma³

et al. 2003

J Pharmacol Sci

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Abstract. Effects of the serotonergic anxiolytic buspirone on plasma glucose and glucoseinduced hyperglycemia were studied in mice. Buspirone did not affect plasma glucose levels of non-fasted mice, while it increased serum insulin levels. In fasted mice, buspirone significantly reduced glucose-induced hyperglycemia and enhanced insulin release elicited by glucose. This suggests that buspirone enhances insulin release, resulting in inhibition of glucose-induced hyperglycemia. The major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP) increased serum insulin levels and induced a slight hypoglycemia in non-fasted mice. 1-PP decreases glucose-induced hyperglycemia and amplifies insulin release elicited by glucose in fasted mice. Since buspirone is mainly metabolized to 1-PP and formation of 1-PP occurs quickly, the inhibitory effect of buspirone on glucose-induced hyperglycemia is likely mediated by 1-PP.

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“…WAY-100635 may not have fully antagonised the effects of buspirone as it is rapidly converted to its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP; Caccia et al, 1986), a potent α 2 -adrenoceptor antagonist, which is able to stimulate cortical dopamine release (Gobert et al, 1999).…”

Section: Effect Of Buspirone and Way-100635mentioning

confidence: 99%

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

et al. 2009

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1-(2-Pyrimidinyl)-Piperazine as Active Metabolite of Buspirone in Man and Rat

Cited by 112 publications

References 7 publications

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Effects of the Serotonergic Anxiolytic Buspirone on Plasma Glucose and Glucose-Induced Hyperglycemia in Mice

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

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