Toxicity of chemotherapy drugs is the leading cause of poor therapeutic outcome in many cancer patients. Gastrointestinal (GI) toxicity and hepatotoxicity are among the most common side effects of ...

BACKGROUND AND PURPOSEGene 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 APPROACHAdult 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 RESULTSCyp3a11 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 IMPLICATIONSLPS 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.

Introduction: Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

Impairment of drug disposition in the liver during inflammation has been attributed to downregulation of gene expression of drug-metabolizing enzymes (DMEs) and drug transporters. Inflammatory responses in the liver are primarily mediated by Toll-like receptors (TLRs). We have recently shown that activation of TLR2 or TLR4 by lipoteichoic acid (LTA) and lipopolysaccharide (LPS), respectively, leads to the downregulation of gene expression of DMEs/transporters. However, the molecular mechanism underlying this downregulation is not fully understood. The xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), regulate the expression of DMEs/transporter genes. Downregulation of DMEs/transporters by LTA or LPS was associated with reduced expression of PXR and CAR genes. To determine the role of CAR, we injected CAR^+/+ and CAR^−/− mice with LTA or LPS, which significantly downregulated (∼40%–60%) RNA levels of the DMEs, cytochrome P450 (Cyp)3a11, Cyp2a4, Cyp2b10, uridine diphosphate glucuronosyltransferase 1a1, amine N-sulfotransferase, and the transporter, multidrug resistance-associated protein 2, in CAR^+/+ mice. Suppression of most of these genes was attenuated in LTA-treated CAR^−/− mice. In contrast, LPS-mediated downregulation of these genes was not attenuated in CAR^−/− mice. Induction of these genes by mouse CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene was sustained in LTA- but not in LPS-treated mice. Similar observations were obtained in humanized CAR mice. We have replicated these results in primary hepatocytes as well. Thus, LPS can downregulate DME/transporter genes in the absence of CAR, whereas the effect of LTA on these genes is attenuated in the absence of CAR, indicating the potential involvement of CAR in LTA-mediated downregulation of DME/transporter genes.