The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

The pharmacokinetics of reboxetine have been investigated in 12 healthy male volunteers after a single 2 mg dose of reboxetine and at steady state, following the last administration of a multiple‐dose regimen (2 mg twice a day for 5½ d). Reboxetine was analysed in plasma and urine samples collected up to 72 h post‐dosing using an HPLC method with UV detection. The urinary excretion rate of 6‐β‐hydroxycortisol, used as a marker for cytochrome P450IIIA activity, was also tested, and any possible alteration was correlated to reboxetine plasma levels. The dosing regimen was well tolerated by all subjects. Reboxetine pharmacokinetic parameters, calculated after the single dose using non‐compartmental analysis, were in good agreement with those obtained in previous studies. Following the multiple‐dosing regimen, no significant deviations from expectation based on linear superposition was observed. The accumulation ratio, based on repeated‐dose/single‐dose ratios of ;Cmax, AUC(0–12 h), and C(12 h) was approximately two. A slight rise was recorded for the average excretion rate of 6‐β‐hydroxycortisol over 48 h by the end of treatment; however, the difference was not statistically significant and the mean excretion rates were within the normal reference range. Thus a significant induction of P450IIIA was not indicated.

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1 The effect of verapamil pre-treatment on the pharmacokinetics and metabolism of antipyrine was studied in eight healthy male volunteers. 2 The oral clearance of antipyrine was decreased from 2.18 to 1.95 1 h-'1 (P < 0.01) by verapamil (80 mg three times daily for 2 days prior to antipyrine administration and 2 days following) while half-life was increased from 13.2 to 15.6 h (P < 0.01). 3 The urinary excretion of norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was decreased by 19.2%, 23.1% and 16.7% respectively (P < 0.05) in the presence of verapamil. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 30%. 4 These results suggest that verapamil is capable of inhibiting oxidative metabolism, a finding which could be of clinical significance for drugs highly dependent upon pathways such as those inhibited in this study for elimination.