Pharmacokinetics of nortriptyline in man after single and multiple oral doses: the predictability of steady-state plasma concentrations from single-dose plasma-level data.

Abstract

Six healthy volunteers were given nortriptyline (NT) in single (1 mg/kg) and multiple (0.4 mg/kg) oral doses with the purpose to study the pharmacokinetics of NT in plasma. The single-dose plasma levels in 3 subjects were applied to a two-compartment open model (Model II) which might be suitable for the disposition kinetics of NT. There were significant (P<0.0005) interindividual differences in the observed mean steady-state plasma concentration,C-0304;, of NT which ranged from 51.7 to 111.0 ng/ml.C-0304; was better correlated to the single-dose plasma clearance rate of NT (r=0.98;P<0.0005) than to the single-dose plasma half-life, (t 1/2)β, (r=0.89;P<0.05). Thus the steady-state plasma level can be accurately predicted from single-dose studies. The apparent volume of distribution of NT at pseudodistribution equilibrium, (Vd)β, varied between 21.1 and 31.1 lit./kg body weight assuming complete absorption of the administered dose. There was no significant correlation (r=0.56) between the single-dose and post steady-state plasma half-lives of NT within individuals. NT does not seem to affect its own metabolismin vivo in man since the single- and multiple-dose plasma clearance rates of the drug were similar within subjects. It is concluded that there might be interindividual differences in both the apparent elimination rate and in the distribution of NT. This may be of importance in the pharmacogenetics of NT.