Cytochrome P450-based drug

Relatively innocuous factors can also sometimes influence liver enzyme activity. For example, the metabolic elimination of the bronchodilator theophylline has been reported to be prolonged in patients with influenza A or adenovirus infections. In 1990, an influenza epidemic in Seattle resulted in the admission of 11 children with high serum levels of theophylline and confirmed drug toxicity. These effects appear to be confined to cytochrome P450-based drug biotransformation. They may be related to the generation of interferons as a result of these infections, which, presumably, are causally related to the inhibitory effect on hydroxylases and demethylases. 

Examples of cytochrome P450-based drug interactions... 

Dickins, M., Galetin, A. and Proctor, N. (2007) Modelling and simulation of pharmacokinetic aspects of cytochrome P450-based metabolic dmd-drug interactions, in Comprehensive Medicinal Chemistry II, vol. 5 (eds J.B. Taylor and D.J. Triggle), Elsevier Ltd, Oxford,... 

Blobaum AL. Mechanism-based inactivation and reversibility is there a new trend in the inactivation of cytochrome P450 enzymes Drug Metab Dispos 2006 34 1-7. 

Tang C, Lin JH, Lu AYH. Metabolism-based drug-drug interactions what determines individual variability in cytochrome P450 induction Drug Met Disp. 2005 33 603-613. 

Khojasteh-Bakht, S.C., L.L Koenigs, R.M. Peter, W.F. Trager, and S.D. Nelson (1998). (R)-(+)-Menthofiiran is a potent, mechanism-based inactivator of human liver cytochrome P450 2A6. Drug Metab. Dispos. 26, 701-704. 

Sridar C, Kobayashi Y, Brevig H, Kent UM, Puppali SG, Rimoldi JM, Hollenbeig PF (2006) Synthesis of substituted phenyl diaziridines and characterization as mechanism-based inactivators of human cytochrome P450 2B6. Drug Metab Dispos 34 1849-1855... 

Zhong W, Uss AS, Ferrari E, Lau JY, Hong Z (2000) De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase. J Virol 74 2017-2022 Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M, McLeod HL (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharma-cokinet 44 279-304... 

Jones, B. C., Ciark, S. E., Human cytochromes P450 and their role in metabolism based drug-drug interactions, in Drug-Drug Interactions. Rodrigues, A. D. (ed.), 2001, Chapter 3, 55-88. Marcel Dekker Inc. New York. 

This chapter describes some of the modified mammalian cell-based systems that have been developed to express intestinal cytochrome P450 enzymes and intestinal transporters. The reader should be aware that other experimental systems, such as transporter expression and drug uptake studies in Xenopus laevis oocytes, have also shown considerable promise [1],... 

Allosteric behavior in cytochrome p450-dependent in vitro drug-drug interactions a prospective based on conformational dynamics. Chemical Research in Toxicology, 14 (4), 338-347. 

Obach, R.S., Walsky, R.L. and Venkatakrishnan, K. (2007) Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions. Drug Metabolism and Disposition, 35 (2), 246—255. 

Jushchyshyn, M.I., Kent, U.M. and Hollenberg, P.F. (2003) The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metabolism and Disposition, 31 (1), 46-52. 

Fontana, E., Dansette, P.M. and Poli, S.M. (2005) Cytochrome P450 enzymes mechanism based inhibitors common sub-structures and reactivity. Current Drug Metabolism, 6, 413 -54. 

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

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