Drug Disposition in Pathophysiological Conditions
Expression and activity of several key drug metabolizing enzymes (DMEs) and transporters are altered in various pathophysiological
conditions, leading to altered drug metabolism and disposition. This can have profound impact on the pharmacotherapy of
widely used clinically relevant medications in terms of safety and efficacy by causing inter-individual variabilities in drug responses.
This review article highlights altered drug disposition in inflammation and infectious diseases, and commonly encountered disorders such
as cancer, obesity/diabetes, fatty liver diseases, cardiovascular diseases and rheumatoid arthritis. Many of the clinically relevant drugs
have a narrow therapeutic index. Thus any changes in the disposition of these drugs may lead to reduced efficacy and increased toxicity.
The implications of changes in DMEs and transporters on the pharmacokinetics/pharmacodynamics of clinically-relevant medications are
also discussed. Inflammation-mediated release of pro-inflammatory cytokines and activation of toll-like receptors (TLRs) are known to
play a major role in down-regulation of DMEs and transporters. Although the mechanism by which this occurs is unclear, several studies
have shown that inflammation-associated cell-signaling pathway and its interaction with basal transcription factors and nuclear receptors
in regulation of DMEs and transporters play a significant role in altered drug metabolism. Altered regulation of DMEs and transporters in
a multitude of disease states will contribute towards future development of powerful in vitro and in vivo tools in predicting the drug response
and opt for better drug design and development. The goal is to facilitate a better understanding of the mechanistic details underlying
the regulation of DMEs and transporters in pathophysiological conditions.
Keywords: Inflammation, drug metabolizing enzymes, drug transporters, pharmacokinetics, Toll-like receptors, cytokines
Rights & PermissionsPrintExport