Induction of cytochrome P450 via upregulation of CAR and PXR: a potential mechanism for altered florfenicol metabolism by macranthoidin B

Introduction: Macranthoidin B (MB) is a primary active component of Methods: Male Sprague-Dawley rats were administered MB (60 mg/kg BW) or sterile water orally for 7 consecutive days. On the 8th day, a single oral dose of florfenicol (25 mg/kg BW) was given. Florfenicol pharmacokinetics were analyzed using ultra-high performance liquid chromatography. The hepatic expression levels of cytochrome P450 (CYP1A2, CYP2C11, CYP3A1), UDP-glucuronosyltransferase (UGT1A1), P-glycoprotein (P-gp), and nuclear receptors, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoid X receptor alpha (RXRα), were quantified via reverse transcription-quantitative polymerase chain reaction and Western blotting (WB). Hepatic CYP1A2 and CYP2C11 activities were measured using a cocktail method. Additionally, the subcellular expression and localization of CAR, PXR, and RXRαin hepatocytes was assessed using WB and immunofluorescence staining. Results: MB significantly reduces the AUC Discussion: These findings suggest that MB-induced alterations in florfenicol pharmacokinetics, particularly its accelerated elimination, may be due to increased expression and activities of CYP1A2 and CYP2C11, with CAR and PXR potentially involved in these regulatory effects. Further investigation is yet needed to fully elucidate the clinical implications of these interactions concerning the efficacy of florfenicol in veterinary medicine.