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A Validated UPLC-MS/MS Method to Determine Free and Total Irinotecan and Its Two Metabolites in Human Plasma After Intravenous Administration of Irinotecan Hydrochloride Liposome Injection

A Validated UPLC-MS/MS Method to Determine Free and Total Irinotecan and Its Two Metabolites in Human Plasma After Intravenous Administration of Irinotecan Hydrochloride Liposome Injection

Quankun Zhuang, Xuemei Liu, Zhuo Sun, Hongyun Wang, Ji Jiang

J Pharm Biomed Anal. 2019 Jun 5;170:112-123.

PMID: 30921645

Abstract:

Irinotecan hydrochloride liposome injection (IHLI) is a formulation of anticancer drug irinotecan hydrochloride (CPT-11) entrapped in the aqueous core of liposomes. To understand the pharmacokinetic property and evaluate the relationship between pharmacokinetics and pharmacodynamics/toxicity of IHLI, it is of prime importance to determine the concentrations of free CPT-11, total CPT-11 and its main metabolites (SN-38 and SN-38 G) in human plasma. In this paper, we developed and validated a sensitive and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to quantify the concentrations of these related substances in human plasma. Free CPT-11, SN-38 and SN-38 G in human plasma were simultaneously separated and extracted by 96-well solid phase extraction (SPE) plate, while total CPT-11 was extracted by protein precipitation (PP) method. The analytes were chromatographed on an Acquity UPLC BEH C18 column and then detected on a Xevo TQ-S tandem mass spectrometer in multiple reactions monitoring (MRM) mode using positive electrospray ionization (ESI). The UPLC-MS/MS method combined with SPE and PP techniques were fully validated in line with existing guidelines issued by regulatory agencies. In brief, all the analytes achieved a satisfactory selectivity and sensitivity in this method. The calibration curves were proved to be linear over the concentration range of 10-10000 ng/mL for total CPT-11, 0.5-1000 ng/mL for free CPT-11, 0.5-200 ng/mL for SN-38 and SN-38 G, respectively. For all the analytes, the intra- and inter-run precisions were less than 11.4% and the accuracies (in terms of RE%) were within -7.7-7.3% except for accuracies of LLOQs were within -15.8 to 7.2%. Besides, carry-over, extraction recovery, matrix effect, dilution integrity, stability and special matrices were also assessed. Finally, the method was successfully applied to a phase I clinical pharmacokinetic study of IHLI in Chinese subjects with advanced solid tumors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP136572093	Irinotecan hydrochloride		136572-09-3	Price

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