Clinical Pharmacokinetics of Nefazodone

Abstract

Nefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration. Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20%. Although there is an 18% increase in nefazodone bioavailability with food, this increase is not clinically significant and nefazodone can be administered without regard to meals. Three pharmacologically active nefazodone metabolites have been identified: hydroxy-nefazodone, triazoledione and m-chlorophenylpiperazine (mCPP). The pharmacokinetics of nefazodone are nonlinear. The increase in plasma concentrations of nefazodone are greater than would be expected if they were proportional to increases in dose. Steady-state plasma concentrations of nefazodone are attained within 4 days of the commencement of administration. The pharmacokinetics of nefazodone are not appreciably altered in patients with renal or mild-to-moderate hepatic impairment. However, nefazodone plasma concentrations are increased in severe hepatic impairment and in the elderly, especially in elderly females. Lower doses of nefazodone may be necessary in these groups. Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2. It is not anticipated that nefazodone will interact with drugs cleared by these isozymes. Indeed, nefazodone did not affect the pharmacokinetics of theophylline, a compound cleared by CYP1A2. Nefazodone is metabolised by and inhibits CYP3A4. Clinically significant interactions have been observed between nefazodone and the benzodiazepines triazolam and alprazolam, cyclosporin and carbamazepine. The potential for a clinically significant interaction between nefazodone and other drugs cleared by CYP3A4 (e.g. terfenadine) should be considered before the coadministration of these compounds. There was an increase in haloperidol plasma concentrations when coadministered with nefazodone; nefazodone pharmacokinetics were not affected after coadministration. No clinically significant interaction was observed when nefazodone was administered with lorazepam, lithium, alcohol, cimetidine, warfarin, theophylline or propranolol.

Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug

“…Consistent with our previous findings, the potency of P4503A4 inhibition by nefazodone significantly increased with time (ϳ1000-fold increase based on the IC 50 values of 15 and 0.015 M for time-independent and time-dependent inhibition). The potent timeand concentration-dependent inactivation of P4503A4 activity by nefazodone is consistent with the numerous examples of pharmacokinetic interactions of nefazodone with P4503A4 substrates and with the nonstationary pharmacokinetics of this drug due to autoinactivation of its elimination mechanism (Greene and Barbhaiya, 1997). In contrast, aripiprazole did not display the marked time-dependent differences in P4503A4 and P4502D6 inhibitory potencies.…”

“…Plausible explanations for this discrepancy may be accounted for by the differences in dose levels and the pharmacokinetics of the two drugs. The absolute oral bioavailability of nefazodone (Greene and Barbhaiya, 1997) and aripiprazole (aripiprazole metabolism data submitted by the manufacturer of the drug to the FDA) in humans has been estimated to be ϳ20 and 87%, respectively. The low oral bioavailability of nefazodone stems from extensive first pass metabolism mediated by P4503A4 in the small intestine and liver.…”

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

“…The principal clearance mechanism of nefazodone in humans involves intestinal and hepatic metabolism catalyzed by cytochrome P450 3A4 (Mayol et al, 1994;Greene and Barbhaiya, 1997;von Moltke et al, 1999;Rotzinger and Baker, 2002). Of particular interest in the many biotransformation pathways of nefazodone is the aromatic hydroxylation, which occurs para to the piperazinyl nitrogen affording p-hydroxynefazodone (metabolite 1) (Fig.…”

Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?

“…In addition, reactive iminium ion intermediates arising from a-C oxidation of the piperazine ring and its downstream metabolites have been characterized as stable cyanide conjugates (Scheme 7) [66]. Nefazodone bioactivation by CYP3A4 is also accompanied by mechanism-based inactivation of the isozyme, which is consistent with DDIs between nefazodone and CYP3A4 substrates [67] [68]. As in the case of nefazodone, para-hydroxybuspirone also represents a major circulating metabolite of the anxiolytic agent buspirone (Scheme 7) [69].…”