Inhibitory effects of non-steroidal anti-inflammatory drugs on human liver microsomal morphine glucuronidation: Implications for drug-drug interaction liability

The inhibitory effects of fifteen NSAIDs from six structurally distinct classes on human liver microsomal morphine glucuronidation were investigated. Ki values of selected NSAIDs were generated and employed to assess DDI liability in vivo. Potent inhibition was observed for mefenamic acid and tolfenamic acid; respective IC50 values for morphine 3- and 6-glucuronidation were 9.2 and 13.5 mu M, and 5.3 and 8.3 mu M. Diclofenac and celecoxib showed moderate inhibition with IC50 values of 78 and 52 mu M, and 83 and 214 mu M, respectively. Estimated IC50 values for the other NSAIDs screened were >100 mu M. Mefenamic acid, diclofenac, and S-naproxen competitively inhibited morphine 3- and 6-glucuronidation, with the Ki values of 11 and 12 mu M, 110 and 76 mu M, and 319 and 650 mu M, respectively. Using the static mechanistic IVIVE approach, an approximate 40% increase in the AUC of morphine was predicted when coadministered with mefenamic acid, whereas the increase was <10% with diclofenac and S-naproxen. PBPK modeling predicted <15% increases in the morphine AUC from diclofenac and S-naproxen inhibition in virtual healthy and cirrhotic subjects. The data suggest that potential clinically significant DDIs arising from NSAID inhibition of morphine glucuronidation is unlikely, with the possible exception of some fenamates. (C) 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.