Drug-metabolizing enzymes and inflammatory responses

Pharmacokinetics properties of drugs are determined by drug-metabolizing enzymes (DMEs), participating in absorption, distribution, and biotransformation. Inflammation is a key feature of many disorders such as metabolic disorders, aging, age-related neurological disorders, and inflammatory bowel diseases. The inflammation is arbitrated by molecular mechanistic synchronization of DMEs and their anomalous expression in different diseases. In autoimmune diseases, the aberrant inflammatory signaling alters the contents and metabolizing capacity of CYP. In rheumatoid arthritis (RA), the level of proinflammatory cytokines is increased in systemic circulation and in synovial joints resulting in the downregulation of mRNA expression of hepatic enzymes such as CYP2B1, CYP2B2, CYP2C6/7, and CYP3A1, proceeding to decrease the effectiveness of statins, calcium channel, and β-blockers drugs. Antibodies against specific cytokines and NSAIDS are suitable therapeutic choice to modulate these aberrant changes in RA. The PXR activation suggests a novel drug target to treat inflammatory bowel diseases along with antiinflammatory agents and antibiotics. In aged population, most of drug detoxification enzymes are downregulated; however, the CYP content regulation is controversial as compared to normal age population. In type 2 diabetes and obesity models, transgenic diabetic models, and obesity-induced diabetes models, the expression of CAR, RXRα, PXR, HNF-4α, and NF-κB is significantly altered resulting in the alteration of drug kinetics. Neuroinflammation-induced neurotoxicity alters the expression of CYP2D6 resulting in altered metabolism of antipsychotic drugs. In this chapter, the underlying molecular mechanism behind these regulations has been discussed to unravel the clear picture and to anticipate the clear drug targets.