1. Pharmacokinetics and apparent Michaelis constant for metabolite conversion of sorafenib in healthy and hepatocellular carcinoma-bearing rats.
- Author
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Cai H, Du X, Deng Y, Cao D, Wang L, Wu Z, Zhang X, Xu J, and Xie B
- Subjects
- Animals, Rats, Male, Chromatography, High Pressure Liquid methods, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Antineoplastic Agents blood, Rats, Sprague-Dawley, Mass Spectrometry, Sorafenib pharmacokinetics, Sorafenib blood, Sorafenib therapeutic use, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular metabolism, Niacinamide analogs & derivatives, Niacinamide blood, Niacinamide pharmacokinetics, Liver Neoplasms drug therapy, Liver Neoplasms metabolism, Phenylurea Compounds pharmacokinetics, Phenylurea Compounds blood, Phenylurea Compounds therapeutic use
- Abstract
Aim: Investigation of the pharmacokinetics of sorafenib (SRF) in rats with hepatocellular carcinoma (HCC). Methods: A reproducible ultra-HPLC-MS method for simultaneous determination of serum SRF, N -hydroxymethyl sorafenib and N -demethylation sorafenib. Results: Both the maximum serum concentrations (2.5-times) and the area under the serum concentration-time curve from 0 h to infinity (4.5-times) of SRF were observed to be significantly higher, with a greater than 3.0-fold decrease in the clearance rate in the HCC-bearing rats compared with these values in healthy animals. Further study revealed approximately 3.8- and 3.2-times increases in the apparent Michaelis constant for N -hydroxymethyl sorafenib and N -demethylation sorafenib conversions in the HCC-bearing rats. Conclusion: The low efficiency for the SRF conversions was a key contributor to the increased serum concentrations of SRF.
- Published
- 2024
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