Systemic exposure of Paracetamol (acetaminophen) was enhanced by quercetin and chrysin co-administration in Wistar rats and in vitro model: risk of liver toxicity

Abstract

Intestinal P-glycoprotein (P-gp) and drug-metabolizing enzymes (DMEs) play an important role in the first-pass-metabolism (FPM) and pharmacokinetics (PK) of majority of drugs. Paracetamol is primarily metabolized by conjugation reactions and a little amount (∼15%) undergoes cytochrome P450 (CYP2E1)-mediated oxidative metabolism produces a hepatotoxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). Quercetin and chrysin are naturally occurring flavonoids, reported as modulators of P-gp and DMEs. Therefore, the objective of this study was to evaluate the effects of quercetin and chrysin on the pharmacokinetics of paracetamol using rats and non-everted gut sacs in vitro. Paracetamol was given orally (100 mg/kg) to rats alone and in combination with quercetin (5, 10 and 20 mg/kg) and chrysin (50, 100 and 200 mg/kg) once daily for 21 consecutive days. Blood samples were collected on the 1st day in single dose pharmacokinetic study (SDS) and on the 21st day in multiple pharmacokinetic studies (MDS). The plasma concentrations of paracetamol were determined by HPLC and PK parameters were calculated by using Kinetica (Version 5.1). The maximum plasma concentration (C_max) and area under the curve (AUC_0–12) of paracetamol was significantly increased by quercetin and chrysin co-administration in SDS and MDS. In non-everted rat gut sac method, the absorption of paracetamol was increased by presence of P-gp inhibitors (verapamil, quinidine and ketoconazole), quercetin and chrysin (50 μg/mL). Our findings suggested that the quercetin and chrysin might be inhibited the P-gp and metabolism of paracetamol; thereby increased the systemic exposure of paracetamol. Further studies are needed to evaluate whether the quercetin or chrysin are involved in the formation of NAPQI by CYP2E1 or not on isolated rat hepatocytes or using cell lines.

• CYP2E1
• flavonoids
• liver toxicity
• P-glycoprotein
• pharmacokinetics

Acknowledgements

The authors are grateful to N. Venkateswarlu, President and P. Lakshmana Rao, Secretary of SAGTE for providing necessary facilities. The authors thank Dr. G. Devalarao, Pricipal and Dr. Buchi. N. Nalluri, Director for PG studies and Research of KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada for their encouragement. The authors are grateful for the generous gifts of paracetamol and verapamil from Lancer Pharmaceutical Pvt. Ltd, Baddi, India and Sipra Labs Ltd, Hyderabad, India, respectively.

Declaration of interest

The authors declare that this research does not have any conflict of interest with anyone or any institute. This study was supported by Siddhartha Academy of General and Technical Education (SAGTE).