Unusual plasma level oscillations of clomipramine in man: a pharmacokinetic and pharmacodynamic dilemma

Abstract

Modern bioanalytic methodology has opened up new opportunities to study drug concentrations in the body and thereby gain an understanding of the pharmacokinetics, pharmacodynamics and hence pathways for the clinical efficacy of various drugs. Plasma clomipramine levels have therefore been studied in normal and depressed subjects after oral and intravenous administration. For eight hours after a single dose plasma clomipramine levels behaved in accordance with known pharmacokinetic principles but thereafter, whichever the route used, there were substantial oscillations, minimal in the morning, maximal early in the afternoon and falling in the late afternoon, peak levels being reached on the second or third day. One possible explanation for these oscillations is that at first much of the drug is stored at binding sites from which it is displaced from time by endogenous substances, competing with the parent drug and causing its release back into the circulation. Future studies should include the behaviour of the metabolite desmethylclomipramine, and the effect of repeated doses of clomipramine.