title: Effect of signal interference from dosing excipients on pharmacokinetic screening of drug candidates by liquid chromatography/mass spectrometry.
abstract: The effect of dosing vehicle excipients such as PEG400, propylene glycol, Tween 80, and hydroxypropyl-beta-cyclodextrin on the accuracy of LC/MS measurements used in pharmacokinetic studies is examined. Using PEG400 as a probe compound, the concentration-time profile of the excipient in plasma from rats dosed both orally and intravenously is determined. These excipient plasma concentrations can result in a 2-5-fold increase in calculated plasma clearance values when the excipient interferes with the quantitation of the dosed compound. This can result in false rejection of a compound in a drug discovery screen. Several plasma purification methods and enhanced chromatographic selectivity are examined as ways to minimize or avoid excipient effects, particularly for very polar compounds. The combination of efficient sample purification and selective chromatography provides an effective way to diminish the significant interference effects of PEG400 and Tween 80. When appropriate, using negative ion mode MS or changing a dosing vehicle excipient, such as substituting propylene glycol for PEG400, provides an alternative approach for eliminating signal interference. The mechanism of excipient-related signal interference is discussed in relation to both competition of gas-phase proton-transfer reactions and high viscosity of dosing excipients.
authors.affiliation: Basic Chemistry and Comparative Medicine, Merck Research Laboratory, Merck & Co., Inc., P.O. Box 2000, RY800-B205, Rahway, New Jersey 07065, USA. sharon_tong@merck.com
authors.forename: Xinchun S
authors.initials: XS
authors.lastname: Tong
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.forename: James V
authors.initials: JV
authors.lastname: Pivnichny
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.forename: Marcie
authors.initials: M
authors.lastname: Donnelly
authors.forename: Ken
authors.initials: K
authors.lastname: Vakerich
authors.forename: Chris
authors.initials: C
authors.lastname: Nunes
authors.forename: Judy
authors.initials: J
authors.lastname: Fenyk-Melody
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D005079:Excipients / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood*; D010599:Pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols