Altered Expression/Activity of Cytochrome P450 (CYP) 3A4 Enzyme: Implications in Drug Safety and Efficacy

Cytochrome P450 (CYP) 3A4 enzyme alterations during diseases. Transcriptional or post-transcriptional down-regulation of hepatic CYP enzymes is a characteristic feature of many diseases including infections; cancer, cardiovascular diseases and liver disorders [1-5]. This disrupts CYP-mediated drug metabolism and clearance in these patients. The major drug metabolizing enzyme (DME) in human liver is CYP3A4, which metabolizes ~60% of drugs [6,7]. Recent studies in pediatric patients show that critical illness is the primary determinant of the clearance of the CYP3A4 substrate, midazolam [8]. Furthermore, diabetic kidney transplant patients had low metabolism of the immunosuppressant, cyclosporine A, likely due to reduced CYP3A4 expression [9]. These clinical observations warrant further studies to understand the molecular mechanism by which human CYP enzymes are down-regulated during diseases.