Kinetic analysis of mutual metabolic inhibition of lidocaine and propranolol in rat liver musomes

The metabolic interaction between lidocaine (LD) and propranolol (PL) was analysed kinetically in rat liver musomes. Employing a very short incubation time of 30 sec, we demonstrated that PL competitively inhibited liver musomal 3-hydroxylation of LD, but did not affect either the formation of monoethylglycinexylidide or methylhydroxylidocaine from LD in PL concentrations up to 1 μM. On the other hand, LD competitively inhibited PL 4-, 5- and 7-hydroxylations, but the inhibition type of LD for PL N-desisopropylation could not be clarified. Comparison of the kinetic data for liver musomes from Wistar and Dark Agouti rats indicated that among the primary metabolic pathways of LD, the V_max value for 3-hydroxylation was markedly less in female Dark Agouti rats. The results suggest that LD 3-hydroxylation and PL ring hydroxylations are mediated by the same isozyme(s) belonging to the CYP2D subfamily.