Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy

Patients with chronic hepatic encephalopathy display monoaminergic perturba tions together with affective symptoms. Thus, these patients belong to a gr oup with a probability of receiving antidepressant drug treatment. The live r impairment may result in pharmacokinetic alterations of the antidepressan t drug, which in turn may affect the already perturbed monoaminergic functi on. Venlafaxine (VEN) was administered as a single subcutaneous challenge t o portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg /kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concen trations of VEN and serotonin as compared to control rats. which had been d emonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats result ed in elevated levels of VEN in serum. brain parenchyma, and brain dialysat e about 300 minutes after the injection. The VEN challenge increased the se rotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose o f VEN administered to experimental hepatic encephalopathy was reduced 50% a s compared to control rats, mainly pharmacokinetic. and possibly also monoa minergic, alterations were observed.