Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4

Ghassabian, Sussan; Gillani, Tina B.; Rawling, Tristan; Crettol, Séverine; Nair, Pramod C.; Murray, Michael T.

doi:10.1208/s12248-018-0262-1

Cited by 11 publications

(8 citation statements)

References 55 publications

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“…Since SR_G plays a crucial role in the enterohepatic circulation of sorafenib [ 5 ], it is more likely that the increased SR_NO/sorafenib exposure ratios are a result of rapid intestinal transit, which shortens the time for SR_G transformation to sorafenib and sorafenib re-absorption, than a result of CYP3A4-mediated DDIs. However, sorafenib itself has shown CYP3A4-inhibitory properties in an in vitro study [ 37 , 40 ], and therefore, metformin could promote the CTP3A4-mediated pathway by alleviating the obstacles (by sorafenib concentration reduction). However, this metabolization hypothesis seems to be less established, especially considering that the direct impact of metformin on CYP3A4 activity remains largely unknown [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additional sorafenib N-oxide exposure (Table 2) is probably a consequence of increased exposure to sorafenib. Considering the fact that both sorafenib and SR_NO exhibit inhibitory effects on CYP3A4 [37], and since atorvastatin itself is its substrate, the induction of CYP3A4 is highly unlikely. Since SR_NO exhibits pharmacological activity, the risk of toxicity is further enhanced.…”

Section: The Influence Of Atorvastatin On the Pharmacokinetics Of Sormentioning

confidence: 99%

“…Sorafenib+atorvastatin treatment may also lead to excessive side effects from atorvastatin, such as hyperglycemia, hepatitis, or musculoskeletal and connective tissue disorders [37], due to an almost doubling of the exposure to atorvastatin (Table 4). Since bioavailability (F) depends on the AUC 0-∞ for extravascular administration and is directly proportional, a significant (p < 0.005) decrease in CL/F and V d /F is consistent with the reported data.…”

Section: The Influence Of Sorafenib On the Pharmacokinetics Of Atorvamentioning

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%

Section: The Influence Of Atorvastatin On the Pharmacokinetics Of Sormentioning

confidence: 99%

Section: The Influence Of Sorafenib On the Pharmacokinetics Of Atorvamentioning

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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“…activity (8). We found recently that CYPs 3A4 and 2D6 were inhibited more effectively by SNO than SOR because the binding of SNO within the active centers of the enzymes was more effective (10,11). These findings suggest that patients that produce more SNO may be at greater risk of pharmacokinetic DDIs.…”

Section: Sno Formation Varies Between Patients Due To Individual Differences In Cyp3a4mentioning

confidence: 91%

Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite

Nair

Gillani

Rawling

et al. 2021

Chemico-Biological Interactions

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The multikinase inhibitor sorafenib (SOR) is a frontline agent in the treatment of hepatocellular and renal cancers. In recent clinical studies SOR has been evaluated increasingly in combination with other oncology agents, such as paclitaxel. However, the use of such combinations could increase the likelihood of pharmacokinetic drug-drug interactions (DDIs) and adverse events. It has been reported that SOR may inhibit a number of human drug oxidation pathways mediated by multiple CYPs. Oxidative biotransformation of SOR generates the pharmacologically active N-oxide metabolite (SNO) that has been shown to accumulate in the serum of some individuals who have been treated with the drug. Recent evidence has suggested that the metabolite SNO is more effective than the parent drug as an inhibitor of some CYP-mediated drug oxidations. Molecular docking studies have shown that SNO is associated with an increase in the binding interactions with active site amino acid residues in these enzymes. SOR has been implicated as an inhibitor of CYP2C8, which is an important catalyst in the oxidative elimination of oncology drugs such as paclitaxel and imatinib; inhibition is potentiated by NADPH-dependent biotransformation of SOR. The present study evaluated the potential contribution of SNO to the inhibition of CYP2C8 and the closely related enzyme CYP2C9. The principal finding to emerge was that SNO was ~2fold more effective than SOR as an inhibitor of CYP2C8-mediated paclitaxel 6hydroxylation in human liver. Both SOR and SNO interacted with active site residues in the catalytic center of CYP2C8; there were four additional hydrogen and halogen bonding interactions involving SNO. In contrast, the binding of SOR and SNO in the active site of CYP2C9 and the capacity to inhibit microsomal losartan oxidation were similar. These findings suggest that SNO has the potential to contribute to pharmacokinetic interactions between SOR and drugs that are substrates for CYP2C8, perhaps in those individuals in whom SNO accumulates.

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“…1), are 3.3 and 5.4 Å from the Fe atom of the heme. Ghassabian et al (2019) similarly reported that the distance of the site of N-oxidation from the heme (Fe atom) was 3.3 Å when sorafenib was docked in another unliganded CYP3A4 structure (pdb code 1TQN). Use of sorafenib as the template for ligand superposition predicted the SOM of 22 of the 31 data set molecules (prediction accuracy of ;71%) ( Table 6).…”

Section: Cyp3a4-mediated Som Prediction Of Protein Kinase Inhibitorsmentioning

confidence: 95%

Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4

Nair

Miners

2019

Drug Metab Dispos

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Protein kinase inhibitors (KIs), which are mainly biotransformed by CYP3A4-catalyzed oxidation, represent a rapidly expanding class of drugs used primarily for the treatment of cancer. Ligand-and structure-based methods were applied here to investigate whether computational approaches may be used to predict the site(s) of metabolism (SOM) of KIs and to identify amino acids within the CYP3A4 active site involved in KI binding. A data set of the experimentally determined SOMs of 31 KIs known to undergo biotransformation by CYP3A4 was collated. The structure-based (molecular docking) approach employed three CYP3A4 X-ray crystal structures to account for structural plasticity of this enzyme. Docking pose and SOM predictivity were influenced by the X-ray crystal template used for docking and the scoring function used for ranking binding poses. The best prediction of SOM (77%) was achieved using the substrate (bromoergocryptine)-bound X-ray crystal template together with the potential of mean force score. Binding interactions of KIs with CYP3A4 active site residues were generally similar to those observed for other substrates of this enzyme. The ligand-based molecular superposition approach, using bromoergocryptine from the X-ray cocrystal structure as a template, poorly predicted (42%) the SOM of KIs, although predictivity improved to 71% when the docked conformation of sorafenib was used as the template. Among the web-based approaches examined, all web servers provided excellent predictivity, with one web server predicting the SOM of 87% of the data set molecules. Computational approaches may be used to predict the SOM of KIs, and presumably other classes of CYP3A4 substrates, but predictivity varies between methods.

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Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4

Cited by 11 publications

References 55 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

Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite

Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4

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