Quantification of topotecan by liquid chromatography-mass spectrometry (LC-MS). Application to intestinal transport using rat everted gut sacs.
Topetecan is an important anti-cancer drug that has recently become available as an oral formulation. In order to study its intestinal absorption in vitro and a potential drug-drug interaction with the anti-emetic ondansetron, a sensitive and accurate method for the analysis of topotecan in biological media was required. We developed a liquid-liquid extraction method at pH 7.0-7.5 with a recovery of 85% and which took into account the complex chemical behaviour of topotecan related to the lactone opening and the keto-enol tautomerism. This enabled us to validate a new specific and sensitive LC-MS method of analysis, with satisfactory inter- and intra-day repeatability and accuracy. The method was applied to a study of topotecan uptake in rat everted gut sacs that showed that, despite being a P-glycoprotein substrate like topotecan, ondansetron did not interfere with topotecan uptake.
EA3035 Clinique et Expérimentale de Médicaments Anticancereux, Institut Claudius Regaud, 31052 Toulouse, France. arellano@cict.fr
Cécile
C
Arellano
Peggy
P
Gandia
Laure
L
Bettuing
John
J
Woodley
Etienne
E
Chatelut
D000818:Animals; D000932:Antiemetics / Q000032:analysis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000032:analysis / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods*; D004347:Drug Interactions; D004386:Duodenum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D016018:Least-Squares Analysis; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008954:Models, Biological; D017294:Ondansetron / Q000032:analysis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D019772:Topotecan / Q000032:analysis* / Q000493:pharmacokinetics*
D000932:Antiemetics; D000970:Antineoplastic Agents; D017294:Ondansetron; D019772:Topotecan