CYP3A4 AND CYP2A6 ACTIVITIES MARKED BY THE METABOLISM OF LIGNOCAINE AND COUMARIN IN PATIENTS WITH LIVER AND KIDNEY-DISEASES AND EPILEPTIC PATIENTS

1 The in vitro hepatic metabolism of lignocaine to monoethylglycinexyl ide (MEGX) is mediated by CYP3A4 and that of coumarin to 7-hydroxycoum arin (7OHC) by CYP2A6. We investigated the usefulness of monitoring se rum MEGX concentrations (after 1 mg kg(-1) lignocaine i.v.) and urinar y 7OHC excretion (after 5 mg coumarin p.o.) to reflect liver function in patients with liver (n = 36), kidney (n = 12) and epileptic (n = 12 ) disease and in control subjects (n = 20). The extent of liver diseas e was assessed using measurements of serum aminoterminal propeptide (P IIINP) and Child-Pugh grades. 2 Serum concentrations of MEGX were decr eased in severe (4.6 +/- 3.0 s.d. ng ml(-1)), moderate (19.1 +/- 11.6 s.d ng ml(-1)) and mild (32.8 +/- 14.2 s.d ng ml(-1)) liver disease as compared with controls (53.4 +/- 15.8 s.d ng ml(-1)). The excretion o f 7OHC over 2 h was decreased in severe (18.0 +/- 10.3 s.d % of dose) and moderate (34.2 +/- 15.6 s.d %), but not in mild (49.7 +/- 19.0 s.d %) liver disease as compared with that in controls (56.2 +/- 11.6 %). 3 In epileptic patients the urinary recovery of 7OHC was increased (2 h value 69.5 +/- 13.2 s.d %) suggesting enzyme induction. In contrast , serum MEGX concentration were low (40.0 +/- 14.1 s.d ng ml(-1)), pos sibly due to competition for CYP3A4 between lignocaine and antiepilept ic drugs. 4 In patients with kidney disease serum MEGX concentration ( 56.5 +/- 26.1 s.d ng ml(-1)) was similar to that in controls. The excr etion rate of 7OHC was reflected in the creatinine clearance (r = 0.66 4). 5 Serum PIIINP values correlated better than Child-Pugh grades wit h serum MEGX concentration and excretion of 7OHC. 6 The case history, extent of liver disease, kidney function and drug therapy must be cons idered when evaluating liver function with probe drugs known to be met abolized by specific hepatic isoforms of cytochrome P450.