Int J Med Sci 2020; 17(3):414-421. doi:10.7150/ijms.38527 This issue

Research Paper

Drug-drug interaction of acetaminophen and roxithromycin with the cocktail of cytochrome P450 and hepatotoxicity in rats

Xiang Liu1, Chen Chen1, Xiaoying Zhang1,2✉

1. Chinese-German Joint Laboratory for Natural Product Research, College of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong 723001, P.R. China.
2. Centre of Molecular and Environmental Biology University of Minho, Department of Biology, Campus de Gualtar, Braga, 4710-057, Portugal.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Liu X, Chen C, Zhang X. Drug-drug interaction of acetaminophen and roxithromycin with the cocktail of cytochrome P450 and hepatotoxicity in rats. Int J Med Sci 2020; 17(3):414-421. doi:10.7150/ijms.38527. Available from

File import instruction


Acetaminophen (APAP) and roxithromycin (ROX) are often used in combination in clinical practice. To evaluate their drug-drug interactions (DDIs) and the hepatotoxicity of co-administration, rats were randomly separated into four groups: Control, APAP (50 mg/kg), ROX (5.5 mg/kg) and APAP-ROX (50 mg/kg and 5.5 mg/kg, respectively). The pharmacokinetic parameters between APAP and ROX were assayed by HPLC, and a cocktail method was used to evaluate the activities of cytochrome (CYP) 450. The liver microsome CYP2E1 protein was detected using Western blot. The levels of plasma parameters, mRNA levels of inflammatory factors (TNF-α, INF-γ, VCAM-1, CXCL-1 and STAT-3) and antioxidant factors (Nrf-2, GSTA, GCLC-1, HO-1 and NQO1) were determined using real-time PCR, along with the observation on histopathological changes in the liver tissue. APAP and ROX co-treatment significantly increased CYP2E1 activity, decreased CYP2D6 activity and prolonged APAP and ROX clearance. Co-treatment increased mRNA expressions of TNF-α, NQO1 and MDA while decreasing GPX and SOD levels. Histopathological evidence showed the changes of liver tissues in terms of structure, size and tight arrangement. This study confirmed that a combination of APAP and ROX inhibited APAP metabolism and that the peak concentration of ROX was delayed. The resulting high level of CYP2E1 may induce oxidative stress and cause liver damage.

Keywords: acetaminophen (APAP), roxithromycin (ROX), cytochrome P450 (CYP450), drug-drug interactions (DDIs), hepatotoxicity