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Xenobiotica
the fate of foreign compounds in biological systems
Volume 51, 2021 - Issue 4
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Animal Pharmacokinetics and Metabolism

Rapid determination of the pharmacokinetics and metabolic fate of gefitinib in the mouse using a combination of UPLC/MS/MS, UPLC/QToF/MS, and ion mobility (IM)-enabled UPLC/QToF/MS

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Pages 434-446 | Received 30 Oct 2020, Accepted 01 Dec 2020, Published online: 08 Feb 2021
 

Abstract

  1. The metabolism and pharmacokinetics of gefitinib (Iressa®, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholino-propoxy)quinazolin-4-amine), a selective thymidylate kinase inhibitor for the epidermal growth factor receptor (EGFR), was studied after IV and PO administration to male C57BL6 mice at 10 and 50mg/kg respectively.

  2. The pharmacokinetics and metabolism of gefitinib were investigated using a range of rapid UHPLC-MS and UHPLC-IM-HRMS methods, using both reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC), to rapidly determine the drugs pharmacokinetics and metabolic fate.

  3. Rapid oral absorption resulted in peak plasma concentrations at 1h of ca. 7µg/mL, that declined with a half-life of 3.8h (2.6h for the IV route), and providing an estimated oral bioavailability of 53%. Gefitinib itself was the major circulating drug-related compound in plasma extracts, with a total of 11 metabolites identified.

  4. The urinary profiles determined using both HILIC and RP-UPLC-IM-MS detected gefitinib and 10 metabolites or 15 metabolites respectively including the detection of a number of novel glucuronide conjugates.

  5. Despite rapid, sub 5min, LC profiling methods being employed metabolite coverage was shown to be high and compared well with that of previous studies.

Disclosure statement

The authors report no declarations of interest.

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