Inhibition of lignocaine metabolism by beta-adrenoceptor antagonists in rat and human liver microsomes.

1. The inhibition of lignocaine metabolism by beta-adrenoceptor antagonists (beta-blockers) was investigated in rat and human liver microsomes. 2. Thirteen beta-blockers (concn. 50 microM) incubated with substrate (4.27 microM) and rat liver microsomes, showed a strong linear correlation between percentage inhibition of lignocaine metabolism and the distribution coefficients of the beta-blockers (r2 = 0.842, P less than 0.001). Similar results for four beta-blockers were obtained using human liver microsomes. 3. In rat liver, which metabolizes lignocaine by aromatic hydroxylation and N-dealkylation, inhibition was selective for the former route. Human liver microsomes metabolize the drug mainly by N-dealkylation and inhibition of this pathway was observed. 4. Liver microsomes from rats treated orally with beta-blockers (0.34 nmol kg per day for 5 days) showed impaired metabolism of lignocaine and impaired formation of 3-hydroxy-lignocaine, despite the absence of significant residues of beta-blocker. 5. 14C-Propanolol was bound irreversibly to rat liver microsomal protein; binding accounted for 4.1 +/- 0.3% (n = 4) dose after 30 min incubation. Exclusion of co-factors and addition of glutathione (GSH, 1 mM) lowered binding by 96% and 70%, respectively. Propanolol inhibited lignocaine metabolism to the same extent in the presence or absence of GSH. The 14C-propanolol bound to liver microsomes from propranolol-treated rats decreased in parallel with inhibition of lignocaine metabolism at 18 to 48 h after pretreatment. 6. These studies indicate at least two mechanisms for the inhibition of lignocaine metabolism by beta-blockers, namely, a 'lipid solubility hypothesis', where the effects may be related to the unchanged drug and a 'metabolite hypothesis', with the possible involvement of an irreversibly bound species.