The oxidation and hypoglycaemic effect of sorafenib in streptozotocin-induced diabetic rats

Karbownik, Agnieszka; Stachowiak, Anna; Urjasz, Hanna; Sobańska, Katarzyna; Szczecińska, Agnieszka; Grabowski, Tomasz; Stanisławiak-Rudowicz, Joanna; Wolc, Anna; Grześkowiak, Edmund; Szałek, Edyta

doi:10.1007/s43440-019-00021-0

Cited by 6 publications

(7 citation statements)

References 24 publications

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“…To properly evaluated our findings, it is important to note the limitations of the conducted studies. First of all, no animal model used in the experiment experienced HCC or T2DM, and as we know from our previous in vivo study with streptozotocin-induced diabetic Wistar rats receiving only sorafenib, T2DM has its impact upon exposure to sorafenib [31]. Additionally, the pharmacokinetic profile of sorafenib, metformin, and atorvastatin may differ between Wistar rats and humans, and the concentrations of sorafenib glucuronide were not measured.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

et al. 2020

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The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib−metformin and sorafenib−atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2−hydroxy atorvastatin (p = 0.0239) and 4−hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.

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Section: Discussionmentioning

confidence: 99%

“…On the other hand, since we used non-diabetic rats, this condition did not enhance the exposure to sorafenib and SR_NO [31], and therefore, we were able to examine potential pharmacokinetic DDIs in this animal model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

et al. 2020

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“…With long-term treatment, sorafenib can also induce the activity of PXR in HCC cells and the expression of drug-resistant genes, which ultimately leads to multidrug resistance ( 18 ). CYP3A4 is an important regulator of sorafenib metabolism and clearance in HCC cells as it can mediate the oxidative metabolism of sorafenib ( 48 ). Our study identified that a microRNA that can act on the 3’UTR of cyp3a4 : miR-4277.…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Sun

Jiang

et al. 2021

Front. Oncol.

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Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

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“…The pharmacokinetics of sorafenib and its metabolites depend on many efflux transporters, such as organic cation transporter−1 (OCT1), organic anion transporting polypeptide 1B1/3 (OATP1B1/3), multidrug resistance-associated protein 2 (MRP2) and protein 3 (MRP3), breast cancer resistance protein (BCRP), and P-glycoprotein (P-pg), which is also an inhibitor [8,9]. Sorafenib has been shown to inhibit P-gp in vitro [3,10] and in vivo [11,12]. After simultaneous administration of sorafenib and P-gp substrates, such as digoxin thereof, the growth of their plasma concentrations cannot be excluded [3,10].…”

Section: Introductionmentioning

confidence: 99%

“…Bearing in mind that sorafenib and probably morphine belong to the P-gp substrates, and sorafenib is also a P-gp inhibitor [10][11][12], the combined use of these drugs may alter their pharmacokinetics, and finally, the safety and efficacy of the cancer therapy. This drug combination in cancer patients may be associated then with drug-drug interactions (DDI) with a higher risk of treatment disruption [42].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

et al. 2021

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A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

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The oxidation and hypoglycaemic effect of sorafenib in streptozotocin-induced diabetic rats

Cited by 6 publications

References 24 publications

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

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