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Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism.
- Source :
-
BMC cancer [BMC Cancer] 2024 Sep 11; Vol. 24 (1), pp. 1131. Date of Electronic Publication: 2024 Sep 11. - Publication Year :
- 2024
-
Abstract
- Background: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort.<br />Methods: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro.<br />Results: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC <subscript>50</subscript> (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC <subscript>50</subscript> of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC <subscript>(0→t)</subscript> , AUC <subscript>(0→∞)</subscript> , and T <subscript>max</subscript> rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib.<br />Conclusions: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Rats
Humans
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Male
Rats, Sprague-Dawley
Tandem Mass Spectrometry
Carcinoma, Renal Cell drug therapy
Carcinoma, Renal Cell metabolism
Kidney Neoplasms drug therapy
Kidney Neoplasms metabolism
Sunitinib pharmacology
Sunitinib pharmacokinetics
Pyridines pharmacokinetics
Pyridines pharmacology
Nitriles pharmacokinetics
Nitriles pharmacology
Microsomes, Liver metabolism
Microsomes, Liver drug effects
Pyrroles pharmacokinetics
Pyrroles pharmacology
Triazoles pharmacokinetics
Triazoles pharmacology
Drug Interactions
Indoles pharmacokinetics
Indoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2407
- Volume :
- 24
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- BMC cancer
- Publication Type :
- Academic Journal
- Accession number :
- 39261851
- Full Text :
- https://doi.org/10.1186/s12885-024-12904-4