Regulation of Drug Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

Abstract

Under conditions of innate immune system activation (i.e., inflammation), the functions of specific cytochrome P450 enzymes, other drug metabolizing enzymes (DMEs), and drug transporters (DTs) are altered in the liver, small intestine, lung, kidney, and central nervous system (CNS). Many of these effects are primarily manifest at the transcriptional/RNA level, leading to corresponding changes in protein levels and function. This not only leads to altered drug and xenobiotic toxicity and action in diseased humans, but also has importance for disease therapy with biologic drugs that target inflammatory mediators or their receptors. Major roles for proinflammatory cytokines such as interleukin‐6 (IL‐6), IL‐1β, and tumor necrosis factor‐α(TNFα) are inferred from the abilities of these agents to affect DMEs and DTs in cultured cells and in vivo , but the in vivo contributions of cytokines to regulation of these proteins in different inflammatory disease states is still poorly understood.

Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation

“…For example, serum interleukin-6 concentrations correlate with the reduced CYP3A4-dependent drug clearance in cancer patients [1,3,4]. Few clinical studies on the impact of inflammation on drug metabolism have been conducted, but several interesting studies have been performed on animals [5]. These animal studies have shown that downregulation of P450 isozymes and P-glycoprotein occurs at the gene transcription level through the mediation of the cytokines.…”

“…These effects can also be mimicked by sterile inflammatory agents. One of the best examples is bacterial lipopolysaccharide, which can downregulate multiple P450 mRNAs in the liver [5].…”

Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice: divergence between tumour and plasma pharmacokinetics

“…It was also of interest that a significant reduction in CL/F and V SS /F was observed with these analogues (particularly the more lipophilic, propyl, and butyl analogues) in the tumour-bearing compared to healthy mice. Many mechanisms may be responsible for the latter, including down-regulation of various drug metabolising enzymes resulting from the increased production of pro-inflammatory cytokines and nitric oxide, or reduction in blood flow to the liver and other tissues [28][29][30].…”

Pharmacokinetics in pregnancy

“…For example, in the late 1970s and early 1980s, decreased theophylline clearance was observed in children with viral infections of the upper respiratory tract and adults after influenza vaccination (Chang et al, 1978;Renton et al, 1980). Subsequent studies linked these findings to the altered expression of drug transporters and CYP450 metabolic enzymes that we now know accompany inflammation (reviewed in Morgan et al, 2008). As previously mentioned, women often enter into pregnancy with pre-existing medical conditions or develop conditions during the course of their pregnancy.…”