CYP3A‐dependent drug metabolism is reduced in bacterial inflammation in mice

BACKGROUND AND PURPOSE Gene expression of Cyp3a11 is reduced by activation of Toll‐like receptors (TLRs) by Gram‐negative or Gram‐positive bacterial components, LPS or lipoteichoic acid (LTA) respectively. The primary adaptor protein in the TLR signalling pathway, TIRAP, plays differential roles in LPS‐ and LTA‐mediated down‐regulations of Cyp3a11 mRNA. Here, we have determined the functional relevance of these findings by pharmacokinetic/pharmacodynamic (PK/PD) analysis of the Cyp3a substrate midazolam in mice. Midazolam is also metabolized by Cyp2c in mice. EXPERIMENTAL APPROACH Adult male C57BL/6, TIRAP+/+ and TIRAP−/− mice were pretreated with saline, LPS (2 mg·kg−1) or LTA (6 mg·kg−1). Cyp3a11 protein expression, activity and PK/PD studies using midazolam were performed. KEY RESULTS Cyp3a11 protein expression in LPS‐ or LTA‐treated mice was reduced by 95% and 60% compared with saline‐treated mice. Cyp3a11 activity was reduced by 70% in LPS‐ or LTA‐treated mice. Plasma AUC of midazolam was increased two‐ to threefold in LPS‐ and LTA‐treated mice. Plasma levels of 1′‐OHMDZ decreased significantly only in LTA‐treated mice. Both LPS and LTA decreased AUC of 1′‐OHMDZ‐glucuronide. In the PD study, sleep time was increased by ∼2‐fold in LPS‐ and LTA‐treated mice. LTA‐mediated decrease in Cyp3a11 protein expression and activity was dependent on TIRAP. In PK/PD correlation, AUC of midazolam was increased only in LPS‐treated mice compared with saline‐treated mice. CONCLUSIONS AND IMPLICATIONS LPS or LTA altered PK/PD of midazolam . This is the first study to demonstrate mechanistic differences in regulation of metabolite formation of a clinically relevant drug by Gram‐negative or Gram‐positive bacterial endotoxins.