Physiological models are good tools to predict rat bioavailability of EF5154 prodrugs from in vitro intestinal parameters.

There are only a few reports on the methods that predict in vivo bioavailability from in vitro intestinal parameters. In the present study, we constructed physiological models where we examined if in vivo rat bioavailability was predictable from in vitro intestinal parameters using prodrugs of EF5154, a potent glycoprotein IIb/IIIa receptor antagonist, and other prodrugs. Apparent fraction absorbed (F(a),pred) was calculated using the physiological models that consist of absorption number calculated from Caco-2 cell membrane permeability (P(app)), and Damkohler number calculated from apparent degradation rate constant (K(dapp)) in rat small intestinal fluid. The predicted rat bioavailability that was calculated from F(a),pred corresponded to the observed rat bioavailability, and root mean square error (RMSE) and squared correlation coefficient (r(2)) were 4.58 and 0.904, respectively, suggesting that the physiological models consisting of the membrane permeability and degradation rate constant are good tools for predicting rat bioavailability of EF5154 prodrugs. As for other prodrugs where the chemical structure of their active forms differs from EF5154, the predicted rat bioavailability was not different from fraction absorbed (or rat bioavailability), suggesting the physiological models are generalized to various prodrugs that are not the substrates for active transporters.

Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats.

The effectiveness of fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI), in the treatment of anxiety disorders, such as obsessive-compulsive, panic and social anxiety disorders, has been confirmed in clinical studies. The hypersensitivity of 5-HT2C receptors has been reported in subjects with these disorders, and SSRIs have been suggested to have therapeutic effects in such cases through the desensitization of the 5-HT2C receptor function. In the present study, we investigated whether chronic administration of fluvoxamine desensitizes 5-HT2C receptors using a putative in vivo rat model of 5-HT2C receptor function. Acute treatment with fluvoxamine or another SSRI, paroxetine, reduced spontaneous locomotion, as observed with the administration of m-chlorophenylpiperazine (mCPP). This effect of fluvoxamine was reversed by treatment with a selective 5-HT2C receptor antagonist, SB 242084. On the other hand, chronic treatment with fluvoxamine or paroxetine inhibited mCPP-induced hypolocomotion, while they had no effects in control rats. In addition, chronic treatment with these drugs had no effects on the mCPP concentration in the rat brain. These results suggest that 5-HT2C receptors are desensitized by chronic treatment with fluvoxamine, as well as paroxetine. Thus, the clinical efficacy of fluvoxamine on anxiety disorders might involve the normalization of the 5-HT2C receptor function.