title: CYP3A-dependent drug metabolism is reduced in bacterial inflammation in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Gandhi
authors.forename: T
authors.initials: T
authors.lastname: Guo
authors.forename: P
authors.initials: P
authors.lastname: Shah
authors.forename: B
authors.initials: B
authors.lastname: Moorthy
authors.forename: D S-L
authors.initials: DS
authors.lastname: Chow
authors.forename: M
authors.initials: M
authors.lastname: Hu
authors.forename: R
authors.initials: R
authors.lastname: Ghose
mesh_terms: D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics* / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics; D013682:Teichoic Acids / Q000494:pharmacology*
chemical_list: D018686:Anesthetics, Intravenous; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D013682:Teichoic Acids; C009900:lipoteichoic acid; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam