Mechanism-based pharmacokinetic–pharmacodynamic modeling of the estrogen-like effect of ginsenoside Rb1 on neural 5-HT in ovariectomized mice

We sought to develop a mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) model to characterize the effects of ginsenoside Rb1 (Rb1) and estradiol (E2) on neural 5-hydroxytryptamine (5-HT) concentration in ovariectomized mice.PK data of Rb1 and E2 were obtained in plasma and brain. Brain levels of 5-HT, tryptophan (TRP), 5-hydroxytryptophan (5-HTP), and 5-hydroxyindoleacetic acid (5-HIAA) were determined after a single intravenous injection of Rb1 (20 mg/kg) and E2 (0.2 mg/kg) in ovariectomized mice. The activities of tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AAAD), and monoamine oxidase (MAO) were also evaluated.Rb1 and E2 elevated neural 5-HT levels via TPH activation and MAO inhibition, respectively. Effects were well described by the mechanism-based PK–PD model. The net effect of increased 5-HT induced by MAO inhibition is greater than TPH activation.The increased brain levels of 5-HT induced by Rb1 and E2 were well described by the present PK–PD model, suggesting the use and further development of this mechanism-based model for the effects of ginsenoside on brain 5-HT levels.