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Sprague-Dawley rats were used as models for single trazodone administration (males), continuous adminstration and dose proportionality experiments (males, females, pregnant females). Plasma and brain tissue were analysed for trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). Fetal exposure to trazodone and m-CPP was assessed and differences in their steady-state plasma concentration were sought between adult males and females. Both trazodone and m-CPP rapidly appeared in plasma and brain tissue following a single intraperitoneal trazodone dose with brain concentrations exceeding those in plasma. Plasma concentrations of m-CPP were lower than those of trazodone but exceeded them in brain tissue. Chronic administration using osmotic mini-pumps revealed a significant linear relationship between trazodone concentration in plasma and brain at steady-state (r=0.96, p&lt;0.0001). No simple relationship was found between plasma and brain tissue concentration for m-CPP. In contrast to observations following single trazodone administration, m-CPP concentrations at steady-state were lower than trazodone concentrations in brain tissue, suggesting a lack of stationarity in the disposition of trazodone over time. No significant differences in plasma or brain tissue drug concentrations relative to administered trazodone dose were observed between male and female rats, nor between pregnant and non-pregnant females. Trazodone and m-CPP were both detected in fetal and placental tissues, with placenta having the highest concentrations. The data suggest that neuropharmacological studies of trazodone could yield different results depending upon the route and schedule of drug administration. Maternally administered trazodone, like many other antidepressants, is distributed to fetal tissues in rodents, reaffirming the need for caution in treating pregnant women with psychoactive drugs.

Pharmacokinetics of trazodone and its major metabolite m-chlorophenylpiperazine in plasma and brain of rats