Drug-mediated inactivation of cytochrome P450.
1. Multiple forms of cytochrome P450 (CYP) catalyse the oxidation of chemicals of endogenous and exogenous origin, including drugs, carcinogens, steroids and eicosanoids. However, this unusual low substrate specificity also makes CYP susceptible to inhibition by a wide range of drugs, leading to pharmacokinetic interactions of potential clinical significance. 2. Some drugs are converted by CYP to reactive metabolites that bind covalently to sites within the active centre of the same CYP. Such mechanism-based inhibition leads to CYP inactivation or complexation. These processes give rise to long-term effects on drug pharmacokinetics, as the inactivated or complexed CYP must be replaced by newly synthesized CYP protein. 3. Drugs that inactivate CYP generally possess recognizable functional groups that are oxidized to reactive products. Thus, drugs with side chains containing unsaturated carbon-carbon bonds and furan ring systems are associated with CYP inactivation. Nitrogen-containing systems may also inactivate CYP. 4. Metabolites formed from drugs containing alkylamino and methylenedioxy functionalities can trap CYP as inert complexes without eliciting inactivation. However, the functional effects of inactivation and complexation on drug pharmacokinetics are indistinguishable. Drugs that elicit CYP complexation include the first generation macrolide antibiotics, but newer analogues appear much safer. Some antidepressants, antiepileptics and tuberculostatic agents have been associated with CYP complexation.
Murray
M
M
Storr Liver Unit, Department of Medicine, University of Sydney, Westmead Hospital, New South Wales, Australia. michaelm@westmed.wh.su.edu.au
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D006418:Heme; D003577:Cytochrome P-450 Enzyme System