Correlation of CYPOR level with pharmacokinetics of caffeine and sorbitol in hepatobiliary pathologies in rats

Abstract

The aim of this study was to investigate the correlation between serum CYPOR levels and the pharmacokinetic parameters of caffeine and sorbitol in laboratory animals with induced hepatobiliary pathologies. Testing this hypothesis will substantiate the possibility of using CYPOR as a surrogate biomarker for predicting individual variability in xenobiotic metabolism in animals with liver disease. The study was conducted on 120 laboratory rats of both sexes weighing 180—220 g. Modeling of hepatobiliary pathologies was carried out in accordance with the «Guidelines for the Experimental (Preclinical) Study of New Pharmacological Substances» edited by R.U. Khabriev (2005). Acute toxic hepatitis was induced by administering methyl trichloride using a patented method (patent RU2821264C1). Fatty liver was modeled using strontium sulfate and a high-fat diet according to patent No. 2766772C1. Ulcerative gastrointestinal lesions were induced by administering indomethacin. Animals were divided into experimental groups based on gender: control (intact), toxic hepatitis, fatty liver, gastrointestinal ulceration, and groups receiving exogenous cytochrome C against the background of the indicated pathologies. CYPOR concentrations in serum were determined by enzyme-linked immunosorbent assay using commercial kits (Cloud-Clone Corp., USA). CYPOR levels were shown to exhibit a strong inverse correlation with caffeine half-life (r=–0,85, p<0,01) and a direct correlation with its clearance (r=0,88, p<0,01), confirming the key role of CYPOR as an obligate electron donor for CYP1A2-mediated metabolism. For sorbitol, correlations with CYPOR were moderate (r=0,55—0,60), indicating the limited applicability of CYPOR as a predictor of the pharmacokinetics of substrates with a predominantly extracytochrome elimination pathway.