Brain‐to‐blood partition and in vivo inhibition of 5‐hydroxytryptamine reuptake and quipazine‐mediated behaviour of nefazodone and its main active metabolites in rodents

The brain/plasma partition of nefazodone, hydroxynefazodone (OHNFZ) and m‐chlorophenyl‐piperazine (mCPP) and their antagonism of p‐chloroamphetamine (PCA)‐induced 5‐hydroxytryptamine (5‐HT) depletion and quipazine‐induced head twitches were compared in rodents. Nefazodone (30 mg kg −1 , i.p.) rapidly entered the brain but concentrations were exceeded by mCPP, the metabolic ratio being 47 and 10 in the mouse and rat respectively. OHNFZ was detectable in plasma but never in brain. Brain concentrations of OHNFZ in the mouse (30 mg kg −1 , i.p.) were less than 10% of those in plasma, confirming a poor blood‐brain barrier penetration. Concentrations of its metabolite mCPP were similar to those after 5 mg kg −1 (i.p.) mCPP. In the mouse, nefazodone (30 mg kg −1 ) antagonized the 5‐HT depleting effect of PCA 2 h after dosing, when it had disappeared from brain but when mCPP concentrations were similar to those after 5 mg kg −1 (i.p.) mCPP. However, mCPP antagonized PCA less than nefazodone. In the rat, nefazodone pretreatment (30 mg kg −1 , 15 min) prevented (97% of inhibition) quipazine‐induced head twitches. The effect was weaker (65% of inhibition) but significant when only mCPP was detected in brain. Analysis of brain concentrations of the two compounds after their ED 50 against quipazine indicated that both contributed to the effect, although nefazodone was more active than mCPP in terms of concentrations required to obtain a comparable reduction of twitches. These findings show that mCPP concentrates in the brain following injection of nefazodone and may play a role in preventing quipazine‐induced behaviour and PCA‐induced 5‐HT depletion. In contrast OHNFZ poorly enters the brain and its in vivo activity is mostly due to its biotransformation to mCPP.British Journal of Pharmacology (1998) 125 , 1617–1623; doi: 10.1038/sj.bjp.0702251