Genetic control of nortriptyline kinetics in man: a study of relatives of propositi with high plasma concentrations.

Considerable variability has been observed in the steady-state plasma concentrations of nortriptyline in psychiatric patients undergoing treatment with the drug (Hammer, Idestrom, and Sjoqvist, 1967). Some patients have been found to have exceptionally high plasma levels forming a mode which was separated from the great majority (Sj6qvist et al, 1968). Nortriptyline (NT) steady-state plasma levels have been shown to be under genetic control (Alexanderson, Price Evans, and Sjoqvist, 1969) in a study of identical and fraternal twins receiving a small daily dose of the drug. The study of Alexanderson et al (1969) did not appear, however, to contain persons who developed exceptionally high steady-state plasma levels. Nortriptyline is easily absorbed from the intestine (Hammer and Sjoqvist, 1967), individual differences in the binding of plasma protein are negligible (Borga et al, 1969), and the renal excretion of unchanged nortriptyline accounts for less than 500 of the daily dose under steady-state conditions (Sjoqvist et al, 1968). The variability in steady-state plasma concentration is therefore presumably due to differences in rate ofmetabolism and apparent volume of distribution (Alexanderson et al, 1969). Investigations in human volunteers suggest that rate of metabolism is the quantitatively most important source of variance (B. Alexanderson and 0. Borga, unpublished observations). The objects of the present study were to attempt to ascertain whether patients achieving very high steady-state NT plasma concentrations do so because of their genetic constitution and whether the manner of genetic control was monogenic or polygenic.