Cytochrome P450 inactivation by pharmaceuticals and phytochemicals: therapeutic relevance.
One of the major clinical concerns is possible drug interactions that can be the result of abrogation of the P450 pathway(s) of metabolism causing toxicity due to elevated exposures of other drugs metabolized by these pathways. When the P450 substrate is catalytically activated to a reactive intermediate, this transient molecule may react with available nucleophilic residues from the enzyme - thereby resulting in the inactivation of the P450. The effects of CYP inactivation on the pharmacokinetics of co-administered drugs or on the inactivator itself depend on complex factors involving the molecular entities, the kinetics of inactivation (K(I), k(inact)), the partition ratio, the zero-order synthesis rate of new enzyme, multiple pathways of metabolism (competing pathways), the dose or exposure, and specific patient characteristics. This review summarizes the catalytic efficiencies of many inactivator drugs along with any consequent clinical relevance. The chemical agents described have been ranked for the kinetic efficiency of inactivation and contrasted with the known clinically relevant drug interactions. This will allow judicious consideration of the many factors that influence the importance of CYP inactivation and their relative contribution to systemic clearance of co-administered drugs. This study allows an improved characterization and dissection of potential physiological interactions with various drugs and nutrients. Knowing more about selective inactivation of cytochrome P450 by common xenobiotics, drugs and phytochemicals allows better understanding of expected interactions with chemotherapeutics and other xenobiotics.
Johnson
William W
WW
Drug Metabolism and Pharmacokinetics, OSI Pharmaceuticals, Boulder, Colorado 80301, USA. bjohnson@osip.com
D000818:Animals; D001665:Binding Sites; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008099:Liver / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000737:chemistry; D028321:Plant Preparations / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D028321:Plant Preparations; D003577:Cytochrome P-450 Enzyme System