Details

Autor(en) / Beteiligte

• Peer, Cody J
• McManus, Terence J
• Hurwitz, Herbert I
• Petros, William P

Titel

Development and utilization of a combined LCaUV and LCaMS/MS method for the simultaneous analysis of tegafur and 5-fluorouracil in human plasma to support a phase I clinical study of oral UFTARG/leucovorin

Ist Teil von

• Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2012-06, Vol.898, p.32-37

Erscheinungsjahr

2012

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Tegafur is a 5-fluorouracil (5-FU) prodrug widely used outside the United States to treat colorectal cancer as well as cancers of the head and neck. The resulting plasma concentrations of tegafur are much higher than those of 5-FU; thus, analytical methods are needed that are sensitive enough to detect low plasma concentrations of 5-FU and robust enough to simultaneously analyze tegafur. Previous LCaMS/MS methods have either failed to demonstrate the ability to simultaneously measure low 5-FU and high tegafur plasma levels, or failed to be applicable in clinical studies. Our goal was to develop a method capable of measuring low concentrations of 5-FU (8a200 ng/ml) and high concentrations of tegafur (800a20,000 ng/ml) in human plasma and to subsequently evaluate the utility of the method in patient samples collected during a phase I clinical study where oral doses of either 200 mg or 300 mg UFTARG/LV (uracil and tegafur in a 4: 1 molar ratio plus leucovorin) were administered. A combined LCaMS/MS and LCaUV method was developed utilizing negative ion atmospheric pressure ionization (API). The method provides an accuracy and precision of <10% and <6%, respectively, for both analytes. Material recoveries from the liquid-liquid extraction technique were 97a110% and 86a91% for tegafur and 5-FU, respectively. Utilization of this method to determine tegafur and 5-FU plasma concentrations followed by noncompartmental pharmacokinetic analyses successfully estimated pharmacokinetic parameters (CMAX, tMAX and AUC0a10 h) in the clinical study patients. Overall, this method is ideal for the simultaneous bioanalysis of low levels of 5-FU and relatively higher levels of its prodrug, tegafur, in human plasma for clinical pharmacokinetic analysis.