title: Fine mapping the spatial distribution and concentration of unlabeled drugs within tissue micro-compartments using imaging mass spectrometry.
abstract: Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 microm intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention.
authors.affiliation: Medical Mass Spectrometry, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nilsson
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Fehniger
authors.forename: Lena
authors.initials: L
authors.lastname: Gustavsson
authors.forename: Malin
authors.initials: M
authors.lastname: Andersson
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kenne
authors.forename: György
authors.initials: G
authors.lastname: Marko-Varga
authors.forename: Per E
authors.initials: PE
authors.lastname: Andrén
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D000069447:Tiotropium Bromide
chemical_list: D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide