Format

Send to

Choose Destination
Br J Pharmacol. 2012 Aug;166(7):2176-87. doi: 10.1111/j.1476-5381.2012.01933.x.

CYP3A-dependent drug metabolism is reduced in bacterial inflammation in mice.

Author information

1
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.

Abstract

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.

PMID:
22394353
PMCID:
PMC3402780
DOI:
10.1111/j.1476-5381.2012.01933.x
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center