HPLC determination of imatinib in plasma and tissues after multiple oral dose administration to mice
1Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia.
Abstract:
Imatinib inhibits Bcr-Abl, c-KIT and PDGFR kinases. It is approved for the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors (GIST) and has further therapeutic potential. Male ICR mice were given imatinib PO (50 or 25 mg/kg, 5 doses every 2 h); euthanized 2 h after the last dose administration; plasma, liver, brain, spleen and kidney were collected and imatinib concentration measured by an optimized HPLC method for quantification in tissues. Methanol (1:1 v/v plasma) and pH 4, 40:30:30 (v/v/v) water-methanol-acetonitrile at 5 ml/g (brain) and 10 ml/g (spleen, kidney, liver) ratio was added to the samples, homogenized, sonicated, centrifuged (15,000 rpm, 5 min, 2 degrees C) and the supernatant injected into an Inertsil CN-3 column (4.6 mm x 150 mm, 5 microm) using 64:35:1 (v/v/v) water-methanol-triethylamine (pH 4.8), flow rate 1 ml/min, 25 degrees C. Imatinib eluted at 7.5 min (268 nm). Linearity: 0.1-50 microg/ml; precision, accuracy, inter- and intra-day variability was within 15%. Recovery was above 95% (plasma), 80% (brain) and 90% (kidney, liver, spleen). Imatinib tissue concentrations were 6-8 folds higher than plasma except brain, where the ratio decreased from 0.24 to 0.08 suggesting limited brain penetration, likely due to blood brain barrier efflux transporters. The extensive distribution supports the expansion of therapeutic applications.
Insights
This study measured imatinib concentrations in mouse tissues. Imatinib distributed widely, with higher levels in organs than plasma, but showed limited brain penetration, suggesting potential for broader therapeutic uses.
Area of Science:
- Pharmacology
- Drug Metabolism and Pharmacokinetics
- Oncology
Background:
- Imatinib is a tyrosine kinase inhibitor approved for treating chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).
- Its efficacy in other cancers suggests potential for expanded therapeutic applications.
- Understanding imatinib's tissue distribution is crucial for optimizing its clinical use.
Purpose of the Study:
- To quantify imatinib concentrations in various tissues of male ICR mice following oral administration.
- To assess the drug's distribution profile and potential for blood-brain barrier penetration.
- To provide data supporting the exploration of imatinib in new therapeutic contexts.
Main Methods:
- Male ICR mice received oral imatinib (25 or 50 mg/kg).
- Plasma, liver, brain, spleen, and kidney were collected 2 hours post-dose.
- Imatinib concentrations were determined using an optimized High-Performance Liquid Chromatography (HPLC) method.
Main Results:
- Imatinib concentrations were 6-8 times higher in the liver, spleen, and kidney compared to plasma.
- Brain tissue showed significantly lower imatinib concentrations, indicating limited penetration across the blood-brain barrier.
- The HPLC method demonstrated linearity, precision, accuracy, and high recovery rates across tissues.
Conclusions:
- Imatinib exhibits extensive distribution into peripheral organs, supporting its broad therapeutic potential.
- Limited brain penetration suggests specific considerations for central nervous system-related indications.
- Further research into imatinib's pharmacokinetic profile can guide its expanded clinical applications.
