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

Abstract

1. The inhibition of lignocaine metabolism by β-adrenoceptor antagonists (β-blockers) was investigated in rat and human liver microsomes.

2. Thirteen β-blockers (concn. 50 μm) incubated with substrate (4.27 μm) and rat liver microsomes, showed a strong linear correlation between percentage inhibition of lignocaine metabolism and the distribution coefficients of the β-blockers (r² = 0.842, P<0.001). Similar results for four β-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 β-blockers (0.34 nmol kg per day for 5 days) showed impaired metabolism of lignocaine and impaired formation of 3-hydroxylignocaine, despite the absence of significant residues of β-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 β-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.