Differential changes in the pharmacokinetics of doxorubicin in diethylnitrosamine-induced hepatocarcinoma model rats

Abstract

1. Hepatocellular carcinoma (HCC) is a malignancy of liver cells. Recent studies have shown that HCC patients often have changes in the activities of transporters and metabolic enzymes, which can considerably affect drug pharmacokinetics and lead to drug toxicity. Doxorubicin (DOX) has been frequently administered in chemotherapy for HCC, but to our knowledge, the effects of HCC on the pharmacokinetics of DOX are unknown.

2. In the present study, following intravenous administration of DOX in diethylnitrosamine-induced HCC rats, the plasma concentration was determined by a UPLC/MS/MS method. The expression of metabolic enzyme and transporters (p-gp, cbr1 and slc22a16) was analyzed by qRT-PCR and western blot.

3. The results showed that the pharmacokinetic parameters AUC, T_1/2, K₁₂ and K₂₁ of DOX were markedly increased, the K₁₀ and CL were significantly decreased in HCC rats. The expression of cbr1 and slc22a16 was markedly decreased, while p-gp was significantly upregulated in HCC rats.

4. These findings suggest that HCC could significantly alter the pharmacokinetic profile of DOX, which may be associated with the decreased expression of cbr1 and slc22a16 rather than the upregulation of p-gp expression.

Keywords:

• Doxorubicin
• pharmacokinetics
• transporters
• metabolic enzymes
• hepatocellular carcinoma

Acknowledgement

We are grateful for the support from the above funds. We are also grateful to Zhi-hong Gong (Waters Technologies Ltd., Shanghai, China) for the UPLC-MS analysis.

Disclosure statement

The authors declare no conflict of interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant (No. 81603189, No. 81860718 and No. U1812403), the Science and Technology Department of Guizhou Province under Grant ([2015]7361, [2017]5718), the Team Project of Guizhou Provincial Science and Technology Department under Grant ([2016]5613\5677), the Project of Central guidance for local science and technology under Grant ([2018]4006), and Guiyang Science and Technology Bureau under Grant ([2017]30-29).