Meloxicam methyl group determines enzyme specificity for thiazole bioactivation compared to sudoxicam

Dustyn A. Barnette, Mary A. Schleiff, Arghya Datta, Noah Flynn, S. Joshua Swamidass, Grover P. Miller

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Meloxicam is a thiazole-containing NSAID that was approved for marketing with favorable clinical outcomes despite being structurally similar to the hepatotoxic sudoxicam. Introduction of a single methyl group on the thiazole results in an overall lower toxic risk, yet the group's impact on P450 isozyme bioactivation is unclear. Through analytical methods, we used inhibitor phenotyping and recombinant P450s to identify contributing P450s, and then measured steady-state kinetics for bioactivation of sudoxicam and meloxicam by the recombinant P450s to determine relative efficiencies. Experiments showed that CYP2C8, 2C19, and 3A4 catalyze sudoxicam bioactivation, and CYP1A2 catalyzes meloxicam bioactivation, indicating that the methyl group not only impacts enzyme affinity for the drugs, but also alters which isozymes catalyze the metabolic pathways. Scaling of relative P450 efficiencies based on average liver concentration revealed that CYP2C8 dominates the sudoxicam bioactivation pathway and CYP2C9 dominates meloxicam detoxification. Dominant P450s were applied for an informatics assessment of electronic health records to identify potential correlations between meloxicam drug-drug interactions and drug-induced liver injury. Overall, our findings provide a cautionary tale on assumed impacts of even simple structural modifications on drug bioactivation while also revealing specific targets for clinical investigations of predictive factors that determine meloxicam-induced idiosyncratic liver injury.

Original languageEnglish
Pages (from-to)10-20
Number of pages11
JournalToxicology Letters
Volume338
DOIs
StatePublished - Mar 1 2021

Keywords

  • Bioactivation
  • Cytochrome P450
  • DILI
  • Epoxidation
  • Liver
  • Meloxicam
  • NSAID
  • Sudoxicam
  • Thiazole
  • Toxicity

Fingerprint

Dive into the research topics of 'Meloxicam methyl group determines enzyme specificity for thiazole bioactivation compared to sudoxicam'. Together they form a unique fingerprint.

Cite this