Acta Pharmacologica Sinica (2009) 30: 646-652; doi: 10.1038/aps.2009.42

Acta Pharmacologica Sinica (2009) 30: 646-652; doi: 10.1038/aps.2009.42

Original Article

Bufalin inhibits CYP 3A 4 activity in vitro and in vivo

Hai-yun LI¹, Wen XU², Xi ZHANG^1,*, Wei-dong ZHANG^1,3,*, Li-wei HU¹

¹Department of Natural Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; ²Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; ³School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, China

Aim: To investigate the inhibitory interactions of bufalin and CYP 3A 4.

Methods: Recombinant human CYP 3A 4 was incubated with bufalin in vitro. Bufalin was administered ig and iv to Wistar rats to further estimate its impact on CYP 3A 4, and midazolam was given to index the activity of CYP 3A 4.

Results: The IC₅₀ of bufalin was 14.52 μmol/L. Bufalin affected CYP 3A 4 activity with increases in AUC_0–t and t_1/2, and decreases in CL and the formation of 1-hydroxy-midazolam after ig or iv administration of midazolam (P<0.05). An increase in C_max after ig bufalin administration (P<0.05) was observed.

Conclusion: Bufalin showed a modest but significant inhibition of CYP 3A 4 both in vitro and in vivo. The likelihood of an interaction between bufalin and the CYP 3A 4-metabolized drugs in human might not be negated.

Keywords: bufalin; cytochrome CYP 3A 4; inhibitory interaction; pharmacokinetics

The work was supported by a program for Changjiang Scholars and the Innovative Research Team in University (No PCSIRT), NCET Foundation, NSFC (No 30725045), National 863 Program (No 2006AA02Z338), China Postdoctoral Science Foundation (No 20070410711), ? 973?/st1:chmetcnv> program of China (No 2007CB507400), Shanghai Leading Academic Discipline Project (No B906) and in part by the Scientific Foundation of Shanghai, China (No 07DZ19728, 06DZ19717, 06DZ19005).

* Correspondence to Prof Wei-dong ZHANG and Dr Xi ZHANG.
Emal WDZhangY@hotmail.com; hkzx11@yahoo.com.cn
Received 2008-12-29 Accepted 2009-03-22

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