Kinetic properties of the metabolism of imipramine and desipramine in isolated rat hepatocytes.

The metabolism of imipramine and desipramine was examined by using isolated rat hepatocytes. The enzyme systems having high-affinity-and-low-capacity and low-affinity-and-high-capacity kinetic properties were found to catalyze aromatic 2-hydroxylations of imipramine and desipramine, and aliphatic N-demethylation of imipramine, respectively. The Km and Vmax values for N-demethylation of imipramine (which formed desipramine) were about 5-10 and 5 times larger than those of both 2-hydroxylations respectively. A competitive inhibition between the 2-hydroxylations of imipramine and desipramine ("parallel pathway interaction") (Chiba M, Fujita S and Suzuki T, J Pharm Sci 77: 944-947, 1988), observed using liver microsomes, was found also in isolated hepatocytes. It was concluded that the characteristics of imipramine metabolism observed in liver microsomes were well reproduced in isolated rat hepatocytes.