In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol

Karbownik, Agnieszka; Miedziaszczyk, Miłosz; Grabowski, Tomasz; Stanisławiak-Rudowicz, Joanna; Jaźwiec, Radosław; Wolc, Anna; Grześkowiak, Edmund; Szałek, Edyta

doi:10.1016/j.biopha.2020.110530

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…In addition, sorafenib can also inhibit the metabolism of canagliflozin by competing with canagliflozin for the same metabolic enzymes, leading to an increase in its blood concentration. According to a study by Karbowniket al [ 46 ], the exposure of tapentadol, which is mainly metabolized by UGT1A9 and UGT2B7, significantly increased when it was co-administered with sorafenib, indicating that UGT can mediate the interactions between the two drugs, which supports our conjecture. Second, sorafenib is not only a substrate for P-gp, BCRP, and MRP, but also an inhibitor of P-gp, while canagliflozin is a substrate for P-gp, BCRP, and MRP.…”

Section: Discussionsupporting

confidence: 88%

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats

Cui¹,

Guo

et al. 2022

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Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups І–Ш were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group Ⅳ received sorafenib and canagliflozin; while group Ⅴ received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and Cmax of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in Vz/F and CLz/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.

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Section: Discussionsupporting

confidence: 88%

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats

Cui¹,

Guo

et al. 2022

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“…The method was successfully applied to investigate pharmacokinetic interactions between SOR and DAPA in rats. The dose of 100 mg/kg for SOR used in our study was selected from the previous studies [ 13 , 14 ], and DAPA was administered at 1 mg/kg, which was selected by converting recommended doses for patients in practice to animal doses [ 42 ]. In addition, UGT1A9 is functional in humans, whereas it is a pseudogene in rats, and Ugt1a7 compensated for the functions of UGT1A9 in rats [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The exposure of SOR may also be affected by enterohepatic recycling as SOR glucuronide is degraded by intestinal β-glucuronidase to become its parent formation again and transported into the blood [ 11 ]. In fact, numerous pharmacokinetic interaction studies of SOR involving the CYP3A4, UGT1A9, and transporters have been reported [ 12 , 13 , 14 ]. More importantly, according to in vitro studies, SOR is one of the most powerful inhibitors of human UGT enzymes identified to date [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats

et al. 2022

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Sorafenib (SOR), an inhibitor of multiple kinases, is a classic targeted drug for advanced hepatocellular carcinoma (HCC) which often coexists with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a sodium–glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Notably, co-administration of SOR with DAPA is common in clinical settings. Uridine diphosphate-glucuronosyltransferase family 1 member A9 (UGT1A9) is involved in the metabolism of SOR and dapagliflozin (DAPA), and SOR is the inhibitor of UGT1A1 and UGT1A9 (in vitro). Therefore, changes in UGT1A9 activity caused by SOR may lead to pharmacokinetic interactions between the two drugs. The objective of the current study was to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of SOR and DAPA in plasma and to evaluate the effect of the co-administration of SOR and DAPA on their individual pharmacokinetic properties and the mechanism involved. The rats were divided into four groups: SOR (100 mg/kg) alone and co-administered with DAPA (1 mg/kg) for seven days, and DAPA (1 mg/kg) alone and co-administered with SOR (100 mg/kg) for seven days. Liquid–liquid extraction (LLE) was performed for plasma sample preparation, and the chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5 mM ammonium acetate (Phase A) and acetonitrile (Phase B). The levels of Ugt1a7 messenger RNA (mRNA) were determined in rat liver and intestine using quantitative real-time polymerase chain reaction (qRT-PCR). The method was successfully applied to the study of pharmacokinetic interactions. DAPA caused a significant decrease in the maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t) of SOR by 41.6% and 50.5%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) significantly increased 2.85- and 1.98-fold, respectively. When co-administering DAPA with SOR, the AUC0–t and the elimination half-life (t1/2Z) of DAPA significantly increased 1.66- and 1.80-fold, respectively, whereas the CLz/F significantly decreased by 40%. Results from qRT-PCR showed that, compared with control, seven days of SOR pretreatment decreased Ugt1a7 expression in both liver and intestine tissue. In contrast, seven days of DAPA pretreatment decreased Ugt1a7 expression only in liver tissue. Therefore, pharmacokinetic interactions exist between long-term use of SOR with DAPA, and UGT1A9 may be the targets mediating the interaction. Active surveillance for the treatment outcomes and adverse reactions are required.

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“…About 50% of cancer patients undergoing active anti-cancer therapy and 90% of patients in the advanced stages experience severe pain [1]. In the clinical practice of cancer therapies, it can be expected that a combination of tyrosine kinase inhibitors (TKIs), such as sorafenib, and opioid analgesics, including morphine, are used, which, according to the WHO guidelines, is the first-choice opioid in the relief of cancer pain [2].…”

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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In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol

Cited by 8 publications

References 44 publications

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats

Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

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