Effects of CYP2C11 gene knockout on the pharmacokinetics and pharmacodynamics of warfarin in rats

Abstract

1. CYP2C11 is the most abundant isoform of cytochrome P450s (CYPs) in male rats and is considered the main enzyme for warfarin metabolism.

2. To further access the in vivo function of CYP2C11 in warfarin metabolism and efficacy, a CYP2C11-null rat model was used to study warfarin metabolism with both in vitro and in vivo approaches. Prothrombin time (PT) of warfarin was also determined.

3. The maximum rate of metabolism (V_max) and intrinsic clearance (CL_int) of liver microsomes from CYP2C11-null males were reduced by 37 and 64%, respectively, compared to those in Sprague Dawley (S-D) rats. The K_m of liver microsomes from CYP2C11-null males was increased by 73% compared to that of S-D rats. The time to reach the maximum plasma concentration (T_max) of warfarin in CYP2C11-null males was significantly delayed compared to that in S-D males, and the CL rate was also reduced. The PT of CYP2C11-null rats was moderately longer than that of S-D rats.

4. In conclusion, the clearance rate of warfarin was mildly decreased and its anticoagulant effect was moderately increased in male rats following CYP2C11 gene knockout. CYP2C11 played a certain role in the clearance and efficacy of warfarin, while it did not seem to be essential.

Keywords:

• CYP2C11
• warfarin
• clearance
• prothrombin time
• gene knockout rat model

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81102522, 81373480 and 81573529), and the Natural Science Foundation of Jiangsu Province (Grant No. BK2011473).