Nefazodone pharmacokinetics and molecular data

Pharmacokinetics
Pharmacodynamics Absorption Metabolites Distribution Protein binding Effect of food Renal disease Liver disease Age/gender effects

Pharmacodynamics
The mechanism of action of Nefazodone, as with other antidepressants, is unknown. Preclinical studies have shown that Nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Nefazodone occupies central 5-HT2 receptors at nanomolar concentrations, and acts as an antagonist at this receptor. Nefazodone was shown to antagonize alpha1-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that Nefazodone had no significant affinity for the following receptors: alpha2 and beta adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine. Return to top

Absorption
Nefazodone is rapidly and completely absorbed but is subject to extensive metabolism, so that its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour and the half-life of Nefazodone is 2 to 4 hours. Return to top

Metabolites
Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered Nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxyNefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out. HO-NEF possesses a pharmacological profile qualitatively and quantitatively similar to that of Nefazodone. mCPP has some similarities to Nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has not yet been well characterized. In addition to the above compounds, several other metabolites were present in plasma but have not been tested for pharmacological activity. Return to top

Distribution
Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In humans the volume of distribution of Nefazodone ranges from 0.22 to 0.87 L/kg. Return to top

Protein binding
At concentrations of 25 to 2500 ng/mL Nefazodone is extensively (> 99%) bound to human plasma proteins in vitro. The administration of 200 mg BID of Nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120 to 150% of the laboratory control. While Nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either Nefazodone or these drugs occurs in vivo. There was a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance. Return to top

Effect of food
Food delays the absorption of Nefazodone and decreases the bioavailability of Nefazodone by approximately 20%. Return to top

Renal disease
In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73 m2) had no effect on steady-state Nefazodone plasma concentrations. Return to top

Liver disease
In a multiple-dose study of patients with liver cirrhosis, the AUC values for Nefazodone and HO-NEF at steady state were approximately 25% greater than those observed in normal volunteers. Return to top

Age/gender effects
After single doses of 300 mg to younger (18 to 45 years) and older patients (> 65 years), Cmax and AUC for Nefazodone and hydroxyNefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10 to 20%. A similar result was seen for gender, with a higher Cmax and AUC in women after single doses but no difference after multiple doses. Treatment with Nefazodone should be initiated at half the usual dose in elderly patients, especially women, but the therapeutic dose range is similar in younger and older patients. Return to top