Disposition of single oral doses of E-10-hydroxynortriptyline in healthy subjects, with some observations on pharmacodynamic effects.

The active and major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% +/- 9.9%. Of the given dose, 51.2% +/- 8.7% was recovered as conjugated E-10-OH-NT and 23.9% +/- 4.3% was recovered as unchanged compound. The plasma t1/2 of E-10-OH-NT was 8.0 +/- 1.2 hours and total plasma clearance was 47.5 +/- 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose-dependent elimination. The mean apparent volume of distribution was 7.7 +/- 2.1 L/kg. Single oral doses of 50 mg E-10-OH-NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P less than 0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E-10-OH-NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E-10-OH-NT call for further phase I studies.