Effect of deuteration of imipramine on its pharmacokinetic properties in the rat.

Imipramine was specifically deuterated in either both aromatic rings or in the N-methyl group, or in both positions, and the pharmacokinetic properties of the products were determined in the rat and compared with those of the non-deuterated analogue. Deuteration of imipramine resulted in a small but significant isotope effect on N-demethylation while aromatic hydroxylation was unaffected. This isotope effect led to a slower rate of systemic clearance, a longer half-life and, when orally administered, enhanced bioavailability. Urinary excretion of didesmethylimipramine-d4, following oral administration of imipramine-d7, was significantly lower than the excretion of didesmethylimipramine following administration of unlabelled imipramine, indicating inhibited demethylation. Similarly, the urinary excretion of desmethylimipramine-d4, didesmethylimipramine-d4 and 2-hydroxydesmethylimipramine-d4 were lower than for the corresponding unlabelled or d7-analogues, indicating the stability of the N-CD3 group. Deuteration had no effect on the pharmacological properties of imipramine as determined in this study.