CYP3A4 induction

Jones, S.A., Moore, L.B., Wisely, G.B. and Kliewer, S.A. (2002) Use of in vitro pregnane X receptor assays to assess CYP3A4 induction potential of drug candidates. Methods in Enzymology, 357, 161-170. 

Noracharttiyapot, W., Nagai, Y, Matsubara, T., Miyata, M., Shimada, M., Nagata, K. and Yamazoe, Y. (2006) Construction of several human-derived stable cell lines displaying distinct profiles of CYP3A4 induction. Drug Metab. Pharmacokinet., 21, 99-108. 

Harmsen, S., Koster, A.S., Beijnen, J.H., Schellens, J.H. and Meijerman, 1. (2008) Comparison of two immortalized human cell lines to study nuclear receptor-mediated CYP3A4 induction. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36, 1166-1171. 

Ripp, S.L., Mills, J.B., Eahmi, O.A., Trevena, K.A., Liras, J.L., Maurer, T.S. and de Morals, S.M. (2006) Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused hy CYP3A4 induction. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 1742—1748. 

Dresser et al. administered St. John s wort (LI 160 300 mg t.i.d.) to 20 ethnically diverse individuals and observed a 44% increase in the systemic clearance of midazolam (Table 3) (98). In contrast, the oral clearance of midazolam was increased 1.7-fold (Table 3). The combined changes in midazolam disposition resulted in a significant reduction in the oral bioavailability of midazolam (Table 3). Gurley et al. examined the one-hour 1-hydroxymidazolam-to-midazolam serum ratio and concluded that St. John s wort administration for 28 days resulted in a significant increase in the ratio, which is indicative of CYP3A4 induction (100). 

Plant NJ, Gibson GG. Evaluation of the toxicological relevance of CYP3A4 induction. Curr Opin Drug Dis Dev 2003 6 50 6. 

Pascussi JM, Drocourt L, Fabre JM, Maurel P, Vilarem MJ (2000a) Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepa-tocytes synergistic increase of CYP3A4 induction by pregnane X receptor activators. Mol Pharmacol 58, 361-372. 

In our laboratory we have further characterized the use of this probe for assessing CYP3A4 induction in cultured human hepatocytes (33,34). In this assay, hepatocytes cultured in 96-well plates are incubated with DFB for 15 minutes. An aliquot of the media is then transferred to a microplate and DFH... 

CYP3A4 Induction Barbiturates, carbamazepine, griseo-fulvin, nafcillin, phenytoin, rifampin, troglitazone Atorvastatin Lovastatin Simvastatin... 

The assay requires the use of confluent or near-confluent hepatocyte cultures. It is well-known that for CYP3A4 induction, cell density is critical. Cell cultures that has low cell densities (e.g. less than 50% confluent) will not be responsive to CYP3A4 inducers such as rifampin. Cell morphol-... 

Tran JQ, Kovacs SJ, McIntosh TS et al. (1999) Morning spot and 24-hour urinary 6-beta-hydroxycortisol to cortisol ratios intrainividual variability and correlation under basal conditions and conditions of CYP3A4 induction. J Clin Pharmacol 39 487 194... 

Notably, CYP3A4 activity can be altered by medications (e.g., CYP3A4 induction by carbamazepine), and CYP3A4 is generally recognized as an important contributor in drug-drug interactions. 

TABLE 8.5 PXR Induction Metric and CYP3A4 Induction In Vivo... 

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