Pharmacokinetic analysis of atorvastatin against experimental hepatotoxicity with special reference to CYP3A4 functioning in rats

To assess the functional status of CYP3A4 substrate in experimental induced hepatotoxicity treated with N-acetyl L-cysteine and Green tea extract for a period of 14 days in rats.

Twenty four Wistar rats were divided into four groups of 6 rats each and induced hepatotoxicity with acetaminophen (500 mg/Kg po once daily for 3 days) in 3 groups. Group 1: Normal control, Group 2, 3 and 4 was administered distilled water (5 ml/kg po), N-acetyl L-cysteine (NAC; 300 mg/Kg po once daily) and Green tea extract (GTE; 100 mg/Kg po once daily), respectively subsequently for 11 days from the last dose of acetaminophen. Atorvastatin (10 mg/kg po) was administered on 15^th day (24 h after conclusion of treatment schedule) in all the groups. The PK studies were conducted in order to evaluate the CYP3A4 activity using the specific substrate atorvastatin in all the groups.

C, t, AUC and MRT of groups 2 max1/20-t and 4 were significantly (p<0.05) increased, while the total body clearance was significantly (p<0.05) decreased compared to normal control after single dose administration of atorvastatin. The kinetic profile of NAC-treated group 3 was comparable to group 1.

All the pharmacokinetic parameters of atorvastatin revealed similar values when hepatotoxic control was compared to Green tea extract treated group, while N-acetyl L-cysteine treated group revealed significant alterations in the kinetic profile that support the functional status of CYP3A4 and hence suggesting hepatoprotective potential of NAC.