The influence of selective serotonin reuptake inhibitors on the plasma andbrain pharmacokinetics of the simplest phenothiazine neuroleptic promazinein the rat

The aim of the present study was to investigate a possible impact of the th ree selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline on the pharmacokinetics of promazine in a steady state in r ats. Promazine was administered twice a day for 2 weeks, alone or jointly w ith one of the antidepressants. Concentrations of promazine and its two mai n metabolites (N-desmethylpromazine and sulfoxide) in the plasma and brain were measured at 30 min and 6 and 12 h after the last dose of the drugs. Al l the investigated SSRIs increased the plasma and brain concentrations of p romazine up to 300% of the control value, their effect being most pronounce d after 30 min and 6 h. Moreover, simultaneous increases in the promazine m etabolites' concentrations and in the promazine-metabolite concentration ra tios were observed. In vitro studies with liver microsomes of rats treated chronically with promazine, SSRIs or their combination did not show any sig nificant changes in the concentrations of cytochromes P-450 and b-5. Howeve r, treatment with fluoxetine, alone or in a combination with promazine, dec reased the rates of promazine N-demethylation and sulfoxidation. A similar effect was observed in the case of promazine and fluvoxamine combination. K inetic studies into promazine metabolism, carried out on control liver micr osomes in the absence or presence of SSRIs added in vitro, demonstrated com petitive inhibition of both N-demethylation and sulfoxidation by the antide pressants. The results of in vivo and in vitro studies indicate the followi ng mechanisms of the observed interactions: (a) competition for an active s ite of promazine N-demethylase and sulfoxidase; (b) adaptive changes in cyt ochrome P-450, produced by chronic treatment with fluoxetine or fluvoxamine ; (c) additionally, increases in the sum of concentrations of promazine+ me tabolites, produced by fluoxetine and sertraline in vivo, suggest simultane ous inhibition of another, not investigated by us, metabolic pathway of pro mazine, e.g, hydroxylation. In conclusion, all the three SSRIs administered chronically in pharmacological doses, increase the concentrations of proma zine in the blood plasma and brain of rats by inhibiting different metaboli c pathways of the neuroleptic. Assuming that similar interactions occur in humans, reduced doses of phenotiazines should be considered when one of the above antidepressants is to be given jointly. (C) 1999 Elsevier Science B. V./ECNP. All rights reserved.