Journal of Animal Research: v.6 n.6, p. 961-966. December 2016 DOI: 10.5958/2277-940X.2016.00138.8 Pharmacokinetic Analysis of Atorvastatin with Silymarin and Rutin in Hepatotoxic Rats with a Special Reference to Functional Status of CYP3A4 Enzyme Mannem Kasi Reddy, Alla Gopala Reddy, Boobalan Gopu*, Muskula Anudeep Reddy, Chitturi Sree Venkat Satish Kumar and Matham Vijay Kumar Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Rajendranagar, Hyderabad, INDIA *Corresponding author: G Boobalan; Email: bhupalvets@gmail.com Received: 07 June, 2016 Accepted: 06 November, 2016 ABSTRACT The study was conducted to assess the functional status of CYP3A4 substrate (atorvastatin) in hepatotoxicity model treated with silymarin and rutin for a period of 14 days in rats. Hepatotoxicity was induced with acetaminophen (500 mg/Kg po once daily for 3 days) in adult male Wistar rats in 3 groups. Group 1: Normal control, Group 2, 3 and 4 were administered distilled water (5 ml/kg po once daily), silymarin (25 mg/Kg po once daily) and rutin (20 mg/Kg po once daily), respectively subsequently for 11 days from the last dose of acetaminophen. On the 15 th day, a CYP3A4 substrate (atorvastatin @ 10 mg/kg po) was administered in all the groups and blood samples were collected at predetermined intervals. Pharmacokinetic interaction studies were conducted for evaluation of CYP3A4 activity using the specific substrate atorvastatin in all the groups. Mean plasma concentration (C max ), half-life (t 1/2 ), area under the plasma concentration time curve (AUC) and mean residence time (MRT) of groups 2 and 4 were significantly (p<0.05) increased and elimination rate constant ( ) was significantly (p<0.05) decreased in acetaminophen treated group as comparison to the normal control group. The kinetic profile of silymarin-treated group 3 was comparable to group 1 for single dose study. All the pharmacokinetic parameters of atorvastatin revealed significant correlations between hepatotoxic control and rutin treated group, while silymarin treated group showed significant alterations in the kinetic profile suggesting its hepatoprotective effect. Keywords: Acetaminophen, Atorvastatin, CYP3A4, Rutin, Silymarin Drug induced hepatotoxicity mimics both acute and chronic forms of liver disease (Kaplowitz, 2004). Drug induced hepatotoxicity accounts for the withdrawal of substantial amounts of clinically approved drugs from the market (Kim et al., 2016). Most of the drugs are metabolized in liver affects the organ’s functional activity causing drug-induced injury (Kaplowitz, 1996). Acetaminophen (N-acetyl-p-aminophenol/APAP; PCM) acts as antipyretic/analgesic agents were commonly used in the treatment of inflammatory conditions (Hinson et al., 2010; Aycan et al., 2014). The microsomal enzyme bio-activates acetaminophen to a reactive metabolite (N-acetyl-para benzoquinone imine/NAPQI) in the liver. NAPQI binds with cellular proteins covalently, deplete hepatic glutathione, and substantially cause centrilobular hepatic necrosis in a dose-dependent fashion (Mitchell et al., 1973; Zhang et al., 2013). Acetaminophen overdose is the most frequent cause of drug-induced acute liver failure and used as a reliable model for assessing the hepatoprotective potential of drugs (Olaleye et al., 2014). Atorvastatin is reversible HMG-CoA reductase inhibitor that are primarily metabolized by cytochrome P450 (CYP3A4) contributes to the reduction of cardiovascular disease worldwide (Shitara and Sugiyama, 2006; Vladutiu, 2008). The co-administration of statins with drugs that inhibit CPY3A4 isoenzyme potentially increase the risk of adverse effects as the metabolism of statins gets slowed down (Rowan, 2010). Many natural products of herbal origin are in use for the treatment of liver ailments (Mitra et al., 2000). Rutin (rutoside, quercetin-3-O-rutinoside and sophorin) is a natural glycoside between the flavonol quercetin and the