GLUCURONIDATION OF DIHYDROCODEINE BY HUMAN LIVER-MICROSOMES AND THE EFFECT OF INHIBITORS

1. Glucuronidation is the major route of metabolism of dihydrocodeine (DHC) and accounts for 25-30% of an oral dose in urine, The kinetics o f DHC-6-glucuronide formation in liver microsomes from five human dono rs and the effect of a number of potential inhibitor drugs were examin ed using a newly developed and validated HPLC assay, 2. The formation of DHC-6-glucuronide exhibited atypical kinetics that conformed to the Hill equation, The mean intrinsic dissociation constant (K-s) and max imum velocity (V-max) values were 1566 mu mol/L and 0.043 mu mol/min p er g, respectively, The K-s and V-max values varied 1.5- and 3.5-fold, respectively, 3. Seven drugs were tested for inhibitory effects on DH C glucuronidation at low (50 mu mol/L) and high (500 mu mol/L) concent rations, At 50 mu mol/L, only diclofenac produced greater than 50% inh ibition, while at concentrations of 500 mu mol/L inhibition was greate r than 35% for diclofenac, amitriptyline, oxazepam, naproxen, chloramp henicol and probenecid, but not paracetamol. 4. The present study foun d little interindividual variation in the activity of human liver micr osomes for glucuronidation of DHC, Comparison of the results from the inhibition studies with those reported previously for codeine and morp hine suggest that the UDP-glucuronosyltransferase isoform UGT2B7 is in volved in the glucuronidation of DHC.