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Abstract
A liquid chromatography–electrospray ionization-time-of-flight/mass spectrometry (LC–ESI-TOF/MS) method was developed for the determination of 4-beta-hydroxycholesterol (4β-HC) in rat plasma, to evaluate cytochrome P450 3A (CYP3A) induction liability of a novel cyclin dependent kinases (CDKs) inhibitor, AGM-130. The method consisted of sample preparation without derivatization reagents for high sensitivity such as picolinyl ester, which could be labor-intensive and time consuming. The 4% bovine serum albumin in phosphate-buffered saline as a surrogate matrix was used in the calibration curve and quality control samples for the determination of 4β-HC. Stable isotope-labeled (SIL) 4β-HC (d7-4β-HC) was used as an internal standard. A quadratic regression (weighted 1/concentration), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range of 3.01–2220 ng/mL for 4β-HC. For quality control samples at 15.0, 165, and 1820 ng/mL from the qualification experiment, the within-run accuracy ranged from 95% to 105% with precision values ≤10% for 4β-HC. This novel LC–ESI-TOF/MS method was successfully applied to evaluate the potential of CYP3A induction by 5′-hydroxy-5-nitro-indirubin oxime (AGM-130) in rat.