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Determination of tegaserod by LC-ESI-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.

Zou JJ, Bian XJ, Ding L, Zhu YB, Fan HW, Xiao DW

Clinical Pharmacology Base, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210006, PR China.

A simple, rapid and sensitive high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) assay for determination of tegaserod in human plasma using diazepam as internal standard (IS) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C(18) column with a mobile phase of methanol: 5mM ammonium acetate (75:25, v/v, adjusting the pH to 3.5 with glacial acetic acid). The quantification of target compounds was obtained by using multiple reaction monitoring (MRM) transitions; m/z 302.5, 173.2 and 285.4, 193.2 were measured in positive mode for tegaserod and internal standard (diazepam), respectively. The lower limit of quantification (LLOQ) was 0.05ng/ml. The calibration curves were linear over the range 0.05-8.0ng/ml (r=0.9996) for tegaserod. The mean absolute recovery of tegaserod was more than 85.56%. Intra- and inter-day variability values were less than 9.21% and 10.02%, respectively. The samples were stable for 8h under room temperature (25 degrees C, three freeze-thaw cycles in 30 days and for 30 days under -70 degrees C). After administration of a single dose of tegaserod maleate 4mg, 6mg and 12mg, respectively, the area under the plasma concentration versus time curve from time 0h to 12h (AUC(0-12)) were (2.89+/-0.88), (5.32+/-1.21) and (9.38+/-3.42) ngh/ml, respectively; peak plasma concentration (C(max)) were (1.25+/-0.53), (2.21+/-0.52) and (4.34+/-1.66) ng/ml, respectively; apparent volume of distribution (V(d)/F) were (6630.5+/-2057.8), (7615.2+/-2242.8) and (7163.7+/-2057.2) l, respectively; clearance rate (CL/F) were (1851.4+/-496.9), (1596.2+/-378.5) and (1894.2+/-459.3) l/h, respectively; time to C(max) (T(max)) were (1.00+/-0.21), (1.05+/-0.28) and (1.04+/-0.16) h, respectively; and elimination half-life (t(1/2)) were (3.11+/-0.78), (3.93+/-0.92) and (3.47+/-0.53) h, respectively; MRT were (3.74+/-0.85), (4.04+/-0.56) and (3.28+/-0.66) h, respectively. The essential pharmacokinetic parameters after oral multiple doses (6mg, b.i.d) were as follows: C(ssmax), (2.72+/-0.61) ng/ml; T(max), (1.10+/-0.25) h; C(ssmin), (0.085+/-0.01) ng/ml; C(av), (0.54+/-0.12) ng/ml; DF, (4.84+/-0.86); AUC(ss), (6.53+/-1.5) ngh/ml. This developed and validated assay method had been successfully applied to a pharmacokinetic study after oral administration of tegaserod maleate in healthy Chinese volunteers at a single dose of 4mg, 6mg and 12mg, respectively. The pharmacokinetic parameters can provide some information for clinical medication.

Published 25 December 2007 in J Chromatogr B Analyt Technol Biomed Life Sci, 861(1): 151-7.
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