Abstract

Since COD (codeine) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro – in vivo extrapolation (IV-IVE) approaches were utilized to identify potential drug-drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD 6-glucuronide (C6G) formation by human liver microsomes (HLM), and demonstrated an 88% reduction in K_m (0.29 vs. 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UGT enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S₅₀ values (0.32 and 0.27 mM) generated in the presence of BSA were comparable to the mean K_m observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with dextropropoxyphene, fluconazole, ketoconazole and methadone. K_i values generated for dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM) and methadone (0.32 μM) predicted 1.60- to 3.66- fold increases in the AUC ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7- catalyzed COD glucuronidation to a similar extent, inhibition by dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with dextropropoxyphene, fluconazole, ketoconazole and methadone potentially affect the intensity and duration of COD analgesia.