P450 inhibition

Other drag molecules can behave as inhibitors of specific cytochrome P450s. Inhibition of cytochrome P450 isozymes can lead to a slowing down of the metab-... 

Human liver microsomes (HLMs) are the most common in vitro sources of enzymes for inhibition studies, and selective probe substrates are required. Recombinant human P450 enzymes have become commercially available. They are widely used for screening, and less selective probe substrate can be used. Hepatocytes and liver slices48 have also been used for P450 inhibition screening to a lesser extent. 

Jenkins, K.M. et al. 2004. Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries. J. Pharm. Biomed. Anal. 34 989. 

Naritomi, Y. et al. Utility of microtiter plate assays for human cytochrome P450 inhibition studies in drug discovery. Drug Metab. Pharmacokin. 19 55. 

Weaver, R. et al. 2003. Cytochrome P450 inhibition using recombinant proteins and mass spectrom-etry/multiple reaction monitoring technology in a cassette incubation. Drug Metab. Dispos. 31 955. 

Di, L. et al. 2006. Comparison of cytochrome P450 inhibition assays for drug discovery using human liver microsomes with LC-MS, rhCYP450 isozymes with fluorescence, and double cocktail with LC/ S. Int. J. Pharmaceut. http //dx.doi.org/10.1016/j.ijpharm.2006.10.039. 

Voorman, R.L., Payne, N.A., Wienkers, L.C., Hauer, M.J. and Sanders, P.E. (2001) Interaction of delavirdine with human liver microsomal cytochrome P450 inhibition of CYP2C9, CYP2C19, and CYP2D6. Drug Metabolism and Disposition, 29 (1), 41—47. 

McGinnity, D.F., Berry, A.J., Kenny J.R., Grime, K. and Riley, R.J. (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metabolism and Disposition, 34 (8), 1291-1300. 

Irreversible Cytochrome P450 Inhibition Common Substructures and Implications for Drug Development... 

Metabolism profiling, and cytochrome P450 inhibition induction in dmg discovery. Curr. Top. Med. Chem. 2001,... 

D. M. High-throughput cytochrome p450 inhibition assays by ultrafast gradient liquid chromatography with tandem mass spectrometry using monolithic columns. Rapid Commun Mass Spectrom 2003, 17, 509-518. 

Cytochrome P450 inhibition Coadministration of delavirdine tablets with certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, calcium channel blockers, ergot alkaloid preparations, amphetamines, and cisapride may result in potentially serious or life-threatening adverse events caused by possible effects of delavirdine on the hepatic metabolism of certain drugs metabolized by CYP3A and... 

Szklarz, G. D. and Halpert, J. R. (1998) Molecular basis of P450 inhibition and activation implications for drug development and drug therapy. Drug Metab. Dispos. 26, 1179-1184. 

Halpert, J. R. (1995) Structural basis of selective cytochrome P450 inhibition. Annu. Rev. Pharmacol. Toxicol. 35, 29-53. 

Obach, R.S., Walsky, R.L, Venkatakrishnan, K., Houston, J.B. and Tremaine, L.M. (2005) vitro cytochrome P450 inhibition data and the prediction of drug-drug interactions qualitative relationships, quantitative predictions, and the rank-order approach. Clinical Pharmacology and Therapeutics, 78, 582-592. 

---