Clinical pharmacokinetics of the irinotecan metabolite 4-piperidinopiperidine and its possible clinical importance.
OBJECTIVE
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 > or = 96.8% and < or = 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 AUC(4PP) 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.
Dodds
H M
HM
University of Queensland, Department of Medicine, Princess Alexandra Hospital, Australia.
Clarke
S J
SJ
Findlay
M
M
Bishop
J F
JF
Robert
J
J
Rivory
L P
LP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D013058:Mass Spectrometry; D010880:Piperidines / Q000493:pharmacokinetics*
C105149:4-(1-piperidino)piperidine; D000972:Antineoplastic Agents, Phytogenic; D010880:Piperidines; D000077146:Irinotecan; D002166:Camptothecin