Drug Disposition in Pathophysiological Conditions

Abstract

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.

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

“…The evidence for the effects of various cytokines on individual CYP enzyme expression and activity (investigated either in vitro or in vivo) is summarized below. For a detailed discussion of the complex mechanisms involved and the differential modulation of different DMEs and drug transporters by different cytokines, the reader is referred to reviews by other authors (Morgan, 1997(Morgan, , 2009Renton, 2000Renton, , 2004Aitken et al, 2006, Aitken andMorgan, 2007;Morgan et al, 2008;Huang et al, 2010;Christensen and Hermann, 2012;Gandhi et al, 2012).…”

“…Alterations in drug pharmacokinetics have been reported in patients with infections and other inflammatory conditions including cancer (Slaviero et al, 2003;Aitken et al, 2006;Morgan et al, 2008;Morgan, 2009;Gandhi et al, 2012). For example, HIV infection has long been reported to change the pharmacokinetics of caffeine, sulfamethoxazole, and fluconazole (Levy, 1997).…”

Experimental Nonalcoholic Steatohepatitis Increases Exposure to Simvastatin Hydroxy Acid by Decreasing Hepatic Organic Anion Transporting Polypeptide Expression

“…Although genetic variation clearly plays a role in the occurrence of ADRs, other factors such as liver diseases are also known to alter drug pharmacokinetics and contribute to the occurrence of ADRs (Verbeeck, 2008;Merrell and Cherrington, 2011;Gandhi et al, 2012;Naik et al, 2013). Liver diseases that impair hepatic function may require dose adjustments to maintain drug concentrations within the therapeutic window and avoid ADRs (Delcò et al, 2005;Verbeeck, 2008).…”

Integrin Receptors Play a Key Role in the Regulation of Hepatic CYP3A

“…The performance of this rather diverse group of enzymes is also highly sensitive to microbial infection (Croyle, 2009;Gandhi et al, 2012). Although the primary paradigm of the field attributed this effect to the production of interferons, cytokines, and chemokines (Zanger and Schwab, 2013), we found that the expression and function of hepatic CYP3A2 in the rat is suppressed for 14 days after a single dose of a recombinant adenovirus, long after these inflammatory mediators dissipate (Callahan et al, 2005).…”