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

Abstract

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...

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effect of Buprenorphine and Fentanyl in Rats: Role of Receptor Equilibration Kinetics

“…Under steady-state conditions, C 100 equals k off /k on ϭ K D and therefore K D and C 100 can be used to compare in vivo potency of buprenorphine and fentanyl. In addition, the relative in vivo potency of drug and metabolite or drugs exhibiting enantiomeric isoforms can be explored using an integrated mechanism-based PK/PD modeling approach (Zuideveld et al, 2002). For instance, it is postulated that buprenorphine's major metabolite, norbuprenorphine, possesses a 50-fold weaker antinociceptive activity than the mother compound (Ohtani et al, 1995).…”

Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

“…The details of the pharmacokinetic-pharmacodynamic experiments in rats have been described previously (10,11). Briefly, 8 days prior to the experiment, the rats were operated upon.…”

“…The pharmacokinetic and pharmacodynamic models and their analyses have been published previously (9)(10)(11). Briefly 2-and 3-compartment pharmacokinetic models were used for the pharmacokinetics of buspirone and flesinoxan, respectively.…”

Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the GlutathioneS-Transferase-π-Specific InhibitorO1-Hexadecyl-γ-glutamyl-S-benzylcysteinyl-D-phenylglycine Ethylester

“…There was no apparent difference between the maximal plasma concentrations of C16C2 and C18C2. The plasma inhibitor concentration was analyzed as a function of time by the nonlinear least-squares program MULTI, according to a two-compartment model (Metzler, 1971;Zuideveld et al, 2002) (Table 4). The volume of central compartment (V c ) and volume of distribution at steady state (V ss ) were the smallest for C16C2, whereas the total body clearance (CL) was the smallest for C18C2 among the synthesized inhibitors (Table 4).…”