Dataset Information

Elucidation of the Differences in Cinobufotalin's Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein.

ABSTRACT: Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin in vivo with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify cinobufotalin in rat plasma. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of cinobufotalin in normal and DEN-injured rats after intravenous (i.v.) injection at a dosage of 2.5 mg/kg. Cinobufotalin pharmacokinetics was well described by the two-compartment pharmacokinetic model and the PK parameters were calculated using WinNonlin 3.3 software. The transfer rate constant of cinobufotalin from the central compartment to the peripheral compartment (k₁₂) in DEN-injured rats was significantly greater than that in normal rats (p < 0.01), accompanied by the shorter half-life for the distribution phase (t_1/2?). Additionally, the elimination rate constant (K₁₀) and clearance (CL) values in DEN-injured rats were significantly higher than that in normal rats (p < 0.05 for K₁₀ and p < 0.001 for CL, respectively). Therefore, the values of areas under concentration - time curve (AUC) and the liver concentration of cinobufotalin in DEN-injured rats was obviously lower than that in normal rats (p < 0.001 and p < 0.01, respectively). This indicated that the PK behaviors of cinobufotalin will be altered in rats with HCC. In addition, P-glycoprotein (P-gp) has shown higher expression in live tissues of DEN-injured rats. Furthermore, cinobufotalin was identified as the substrate of P-gp using MDCK II and MDCK-MDR1 cell models for the first time. Consequently, P-gp will play an important role in the disposition of cinobufotalin in vivo, which provided a new combination therapy for the clinical treatment of HCC.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6533572 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Elucidation of the Differences in Cinobufotalin's Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein.

Zhang Xiaojing X Liu Tong T Zhang Yidan Y Liu Fanye F Li Haiying H Fang Dong D Wang Chaojie C Sun Hua H Xie Songqiang S

Frontiers in pharmacology 20190517

Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin <i>in vivo</i> with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance l ...[more]

PMID: 31156437

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Project description:BackgroundPharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development.MethodsSeparate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry.ResultsThe pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin.ConclusionThe results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development.Clinical trial registrationhttp://www.chinadrugtrials.org.cn/eap/main, identifiers CTR20130704 and CTR20190127.

Dataset Information

Elucidation of the Differences in Cinobufotalin's Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein.

Publications

Elucidation of the Differences in Cinobufotalin's Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein.

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