Antidepressant drug effects in vivo: Focus on pharmacokinetic and pharmacodynamic responses in different experimental paradigms

Detta är en avhandling från Cecilia Wikell, Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden

Sammanfattning: Pharmacokinetic and pharmacodynamic activities of the antidepressants venlafaxine (VEN) and citalopram (CIT) were investigated in the portacaval shunted (PCS) rat, a model of chronic hepatic encephalopathy (HE), and normal/control rats. The levels of VEN in serum and brain were higher in PCS rats than in controls after a single injection and chronic treatment with VEN (10 mg/kg). After reducing the dose by 50% to PCS rats (i.e. 5 mg/kg, single injection), the levels of VEN were still higher in experimental HE than in controls. Furthermore, since the T1/2 for VEN was prolonged by 80% in experimental HE, the results suggest that liver-insufficient patients may have to be treated with both reduced doses and with longer dosing intervals than patients with intact liver function. The S/R ratio of the enantiomers of VEN differed between serum and brain in both experimental HE and controls, but the ratio was not altered in experimental HE versus controls. This could be reassuring regarding drug safety for VEN in patients suffering from HE. There were no major differences in S/R ratio of CIT between serum and brain of normal rats. The levels of 5-HT in brain dialysis samples were higher in the PCS rats compared to controls following administration of 10 mg/kg to both groups. However, the 5-HT levels were not higher in experimental HE compared to normal rats when the dose of VEN was reduced in PCS rats. In conclusion, both pharmacokinetic and pharmacodynamic alterations were observed in experimental HE after administration of the antidepressant drugs VEN and CIT.

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