Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics

Abstract

Infection and inflammation are associated with down-regulations of hepatic and extrahepatic cytochrome P450s, as well as other drug metabolizing enzymes and transporters. We will review the genesis of inflammatory reactions, and discuss the relevance of the inflammatory regulation of P450 enzymes observations to clinical drug-disease and drug-drug interactions. Mechanistically, understanding the enzyme specificity and mechanisms of regulation will allow us to make better decisions about drug dosage regimens when a patient’s inflammatory status changes.

Figure 1

Effect of onset or amelioration of inflammation on hepatic cytochrome P450 expression or activity, and on steady state drug concentrations in plasma. The left panel, depicts a patient on a stable drug regimen who becomes afflicted with an acute inflammatory or infectious disease. Down-regulation of the hepatic P450(s) responsible for clearing the drug results in reduced clearance and elevated means steady state plasma concentrations of drug. The right panel depicts the theoretical situation of a patient with a chronic inflammatory condition who is on a stable drug regimen. When the patient is treated with an anti-inflammatory drug (e.g. one targeted towards a proinflammatory cytokine), the down-regulation of the relevant P450 enzyme is relieved, drug clearance increases, and means steady state plasma concentrations of drug decrease.

Figure 2

Comparison of the effects of LPS injection or infection with Citrobacter rodentium on hepatic P450 enzyme mRNAs. Data are taken from published studies in which C3H/HeOuJ mice were either infected with C. rodentium and killed 6 days later (33), or injected with 1 mg/kg LPS and killed 12 h later (16). The mRNA levels in the respective control groups were set at 1 (dotted line) for each P450 mRNA, and the expression in the treated groups is expressed as a fraction of control. Values are mean ± S.E.M., *, p<0.05 compared to control.