“…A small but significant isotope effect (1.33) on the metabolic conversion of imipramine to DMI was thus observed, and this was consistent with the majority of isotope effects observed for N-demethylation reactions (magnitude <2) which have produced modified pharmacological properties (Elison et al, 1963;Abdel-Monem, 1975;Nelson et al, 1975 (Bax et al, 1980). In part, this is related to a progressive increase in plasma binding of the drug (Routledge et al, 1980) but studies in dogs also suggest a lowering of intrinsic clearance with time (Le Lorier et al, 1977;Vicuna et al, 1978).…”