title: Determination of the total drug-related chlorine and bromine contents in human blood plasma using high performance liquid chromatography-tandem ICP-mass spectrometry (HPLC-ICP-MS/MS).
abstract: A fast, accurate and precise method for the separation and determination of the total contents of drug-related Cl and Br in human blood plasma, based on high performance liquid chromatography - inductively coupled plasma - tandem mass spectrometry (HPLC-ICP-MS/MS), has been developed. The novel approach was proved to be a suitable alternative to the presently used standard methodology (i.e. based on a radiolabelled version of the drug molecule and radiodetection), while eliminating the disadvantages of the latter. Interference-free determination of (35)Cl has been accomplished via ICP-MS/MS using H2 as reaction gas and monitoring the (35)ClH2(+) reaction product at mass-to-charge ratio of 37. Br could be measured "on mass" at a mass-to-charge of 79. HPLC was relied on for the separation of the drug-related entities from the substantial amount of inorganic Cl. The method developed was found to be sufficiently precise (repeatability <10% RSD) and accurate (recovery between 95 and 105%) and shows a linear dynamic range (R(2)>0.990) from the limit of quantification (0.05 and 0.01 mg/L for Cl and Br in blood plasma, respectively) to at least 5 and 1mg/L for Cl and Br, respectively. Quantification via either external or internal standard calibration provides reliable results for both elements. As a proof-of-concept, human blood plasma samples from a clinical study involving a newly developed Cl- and Br-containing active pharmaceutical ingredient were analysed and the total drug exposure was successfully described. Cross-validation was achieved by comparing the results obtained on Cl- and on Br-basis.
authors.affiliation: Ghent University, Department of Analytical Chemistry, Krijgslaan 281-S12, 9000 Ghent, Belgium.
authors.forename: Balázs
authors.initials: B
authors.lastname: Klencsár
authors.affiliation: Ghent University, Department of Analytical Chemistry, Krijgslaan 281-S12, 9000 Ghent, Belgium.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bolea-Fernandez
authors.affiliation: Ghent University, Department of Analytical Chemistry, Krijgslaan 281-S12, 9000 Ghent, Belgium.
authors.forename: María R
authors.initials: MR
authors.lastname: Flórez
authors.affiliation: Ghent University, Department of Analytical Chemistry, Krijgslaan 281-S12, 9000 Ghent, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Balcaen
authors.affiliation: Janssen R&D, Pharmacokinetics, Dynamics & Metabolism, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.affiliation: Ghent University, Department of Organic and Macromolecular Chemistry, Krijgslaan 281-S4-bis, 9000 Ghent, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lynen
authors.affiliation: Ghent University, Department of Analytical Chemistry, Krijgslaan 281-S12, 9000 Ghent, Belgium. Electronic address: Frank.Vanhaecke@UGent.be.
authors.forename: Frank
authors.initials: F
authors.lastname: Vanhaecke
mesh_terms: D001966:Bromine / Q000097:blood*; D002713:Chlorine / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D002713:Chlorine; D001966:Bromine
keywords: Drug metabolism; Inductively coupled plasma—; Total drug exposure; tandem mass spectrometry