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

Abstract

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.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.The results showed that the pharmacokinetic parameters AUC, T1/2, 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.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.