Clinical pharmacokinetics of the irinotecan metabolite 4-piperidinopiperidine and its possible clinical importance

Purpose: To investigate the clinical relevance of 4-piperidinopiperidine (4PP) in the activity of irinotecan (CPT-11), a high-performance liquid chromatography-turboionspray-tandem mass spectrometry assay for plasma 4PP was developed. Methods: Plasma samples were prepared for analysis following C18 solid-phase extraction. Chromatography was performed on a Waters Nova-Pak Phenyl column. Selected reaction monitoring with the mass transitions m/z 169.2 → 84.2 and 139.2 → 98.1 was used for the detection of 4PP and the internal standard (IS), 1-piperidineproprionitrile, respectively. Results: The assay was linear from 14.8 to 591.0 nM with absolute recoveries of 4PP (59.1 nM) and IS (143.7 nM) of 85.7% (n=10) and 86.7% (n=10), respectively. The accuracy and imprecision of the method (total) was ≥96.8% and ≤8.5% over the concentration range studied, respectively. 4PP was detectable in plasma following the administration of 125, 350, 500 mg/m2 and 600 mg/m2 CPT-11 to patients, with AUC4PP correlated with the dose (r2= 0.66). Plasma concentrations of 4PP declined slowly with a long terminal half-life (33.4 ± 17.1 h). Conclusions: Overall, the concentrations of 4PP in plasma were in the sub-micromolar range (<206.9 nM) and substantially lower than those capable of inducing apoptosis of cancer cells.