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A study of common discovery dosing formulation components and their potential for causing time‐dependent matrix effects in high‐performance liquid chromatography tandem mass spectrometry assays
Author(s) -
Xu Xiaoying,
Mei Hong,
Wang Shiyong,
Zhou Qiao,
Wang Ganfeng,
Broske Lisa,
Pena Adrienne,
Korfmacher Walter A.
Publication year - 2005
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.2102
Subject(s) - chemistry , chromatography , protein precipitation , mass spectrometry , tandem mass spectrometry , matrix (chemical analysis) , ion suppression in liquid chromatography–mass spectrometry , pharmacokinetics , high performance liquid chromatography , liquid chromatography–mass spectrometry , elution , dosing , pharmacology , medicine , organic chemistry
Hydroxyproyl‐ β ‐cyclodextran (HPBCD), methyl cellulose (MC), Tween 80 and PEG400 are commonly used in dosing formulations in pharmacokinetic (PK) studies during the early drug discovery stage. A series of studies was designed to evaluate the potential matrix effects of these dosing vehicles when the samples are assayed by high‐performance liquid chromatography combined with tandem mass spectrometry (HPLC/MS/MS). These dosing vehicles were dosed into the rats via either an intravenous (IV) or an oral route (PO) and plasma samples were collected for a 24‐h post‐dose period. Five test compounds with CLog P values ranging from 0.9 to 5.4 were spiked into the collected rat plasma. After protein precipitation, these samples were analyzed using a generic fast‐gradient HPLC/MS/MS method. Three popular mass spectrometers (Thermo‐Finnigan Quantum with ESI and APCI, AB‐Sciex API 3000 with ESI and APCI, and Waters‐Micromass Quattro Ultima with ESI) were used to test these plasma samples. Results indicated that there was no observed matrix effect for all five compounds when 20% HPBCD or 0.4% MC was used as the vehicle in either the IV or the PO route, respectively. In addition, 0.1% Tween 80 dosed either IV or PO caused significant ion suppression (50–80%, compared to results obtained from plasma samples free from vehicles) for compounds that eluted at the beginning of the chromatogram. Also, PEG400 when used in an oral formulation caused significant ion suppression (30–50%) for early eluting compounds. These matrix effects were not only ionization mode (ESI or APCI) dependent, but also source design (Thermo‐Finnigan, AB‐Sciex or Waters‐Micromass) dependent. Overall, the APCI mode proved to be less vulnerable to matrix effects than the ESI mode. Some possible mechanisms of these matrix effects are proposed and simple strategies to avoid these matrix effects are discussed. Copyright © 2005 John Wiley & Sons, Ltd.