A LC–MS/MS method for therapeutic drug monitoring of sorafenib, regorafenib and their active metabolites in patients with hepatocellular carcinoma

Iacuzzi, Valentina; Zanchetta, Martina; Gagno, Sara; Poetto, Ariana Soledad; Orleni, Marco; Marangon, Elena; Guardascione, Michela; Foltran, Luisa; Posocco, Bianca; Toffoli, Giuseppe

doi:10.1016/j.jpba.2020.113358

Cited by 17 publications

(9 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to a published article regarding the LC-MS/MS method, we analyzed and determined the SOR concentration in rat plasma with minor modifications ( Allard et al, 2017 ; Iacuzzi et al, 2020 ). The Qtrap 4500 mass spectrometer equipped with a turbo ionspray interface connected to the ExionLC analytical system (AB Sciex, United States) was adopted for analysis.…”

Section: Methodsmentioning

confidence: 99%

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

et al. 2021

View full text Add to dashboard Cite

Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses.Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model.Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model.Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study.

show abstract

Section: Methodsmentioning

confidence: 99%

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Several methods have been developed to determine the blood concentration of SOR [ 26 , 27 , 28 , 29 ]. However, these methods presented some limitations regarding a narrow linearity range [ 26 , 27 ], a lengthy analysis time [ 27 ], and a cumbersome sample preparation [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…There was a validated method for therapeutic drug monitoring of SOR with a wide linear range and enough sensitivity. However, the analysis time was too long to be used for the analysis of large numbers of samples [ 29 ]. Similarly, several methods can be used to determine the blood concentration of DAPA [ 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

Molecules

View full text Add to dashboard Cite

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.

show abstract

“…Accordingly, a suitable pretreatment technique needs to be selected to improve the purification efficiency and reduce the effect of the impurities. Based on the detection of TKIs, the commonly used pretreatment techniques include protein precipitation (PP) ( Tibben et al, 2019 ; Ferrer et al, 2020 ; Iacuzzi et al, 2020 ; Krens et al, 2020 ; Aghai et al, 2021 ), liquid-liquid extraction (LLE) ( Ni et al, 2017 ; Guan et al, 2019 ; Ezzeldin et al, 2020 ), salinization-assisted liquid-liquid extraction (SALLE) ( Zhou et al, 2021 ), and solid-liquid extraction (SLE) ( Sueshige et al, 2021 ), among others. While QuEChERS is an emerging pretreatment technique derived from dispersive solid-phase extraction (dSPE), it was initially applied in the field of pesticide residues.…”

Section: Introductionmentioning

confidence: 99%

Rapid Determination of 9 Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma in Human Plasma by QuEChERS-UPLC-MS/MS

et al. 2022

View full text Add to dashboard Cite

A reliable and rapid method employing QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) pretreatment coupled with ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) was successfully developed and validated for the analysis of nine tyrosine kinase inhibitors (TKIs) in human plasma. Biological samples were extracted with acetonitrile and salted out with 350 mg of anhydrous magnesium sulfate (MgSO4), followed by purification with 40 mg of ethyl enediamine-N-propylsilane (PSA) adsorbents. All analytes and internal standards (IS) were separated on the Hypersil GOLD VANQUISH C18 (2.1 mm × 100 mm, 1.9 μM) column using the mobile phases composed of acetonitrile (phase A) and 0.1% formic acid in water (phase B) for 8.0 min. Detection was performed by selection reaction monitoring (SRM) in the positive ion electrospray mode. Lenvatinib, sorafenib, cabozantinib, apatinib, gefitinib, regorafenib, and anlotinib rendered good linearity over the range of 0.1–10 ng/ml, and 1–100 ng/ml for tivantinib and galunisertib. All linear correlation coefficients for all standard curves were ≥ 0.9966. The limits of detection (LOD) and the limits of quantitation (LOQ) ranged from 0.003 to 0.11 ng/ml and 0.01–0.37 ng/ml, respectively. The method was deemed satisfactory with an accuracy of -7.34–6.64%, selectivity, matrix effect (ME) of 90.48–107.77%, recovery, and stability. The proposed method is simple, efficient, reliable, and applicable for the detection of TKIs in human plasma samples as well as for providing a reference for the clinical adjustment of drug administration regimen by monitoring the drug concentrations in the plasma of patients.

show abstract

A LC–MS/MS method for therapeutic drug monitoring of sorafenib, regorafenib and their active metabolites in patients with hepatocellular carcinoma

Cited by 17 publications

References 18 publications

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

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

Rapid Determination of 9 Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma in Human Plasma by QuEChERS-UPLC-MS/MS

Contact Info

Product

Resources

About