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

Purpose: To investigate the clinical relevance of 4-piperidinopiperidine (4 PP) in the activity of irinotecan (CPT-11), a high-performance liquid chrom atography-turboionspray-tandem mass spectrometry assay for plasma 4PP was d eveloped. Methods: Plasma samples were prepared for analysis following C18 solid-phase extraction. Chromatography was performed on a Waters Nova-Pak P henyl column. Selected reaction monitoring with the mass transitions m/z 16 9.2 --> 84.2 and 139.2 --> 98.1 was used for the detection of 4PP and the i nternal standard (IS), 1-piperidineproprionitrile, respectively. Results: T he 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), respective ly. The accuracy and imprecision of the method (total) was greater than or equal to 96.8% and less than or equal to 8.5% over the concentration range studied, respectively. 4PP was detectable in plasma following the administr ation of 125, 350, 500 mg/m(2) and 600 mg/m(2) CPT-11 to patients, with AUC (4PP) correlated with the dose (r(2) = 0.66). Plasma concentrations of 4PP declined slowly with a long terminal half-life(33.4 +/- 17.1 h). Conclusion s: Overall, the concentrations of 4PP in plasma were in the sub-micromolar range (<206.9 nM) and substantially lower than those capable of inducing ap optosis of cancer cells.