SLAS Discovery - Special Issue on Advances in MALDI Mass Spectrometry for Drug Discovery - Volume 22 Issue 10 - December 2017 - 1239

724780
research-article2017

JBXXXX10.1177/2472555217724780SLAS DISCOVERY: Advancing Life Sciences R&DGrove et al.

Original Research

Application of Imaging Mass Spectrometry
to Assess Ocular Drug Transit

SLAS Discovery
2017, Vol. 22(10) 1239-1245
© 2017 Society for Laboratory
Automation and Screening
https://doi.org/10.1177/2472555217724780
DOI: 10.1177/2472555217724780
journals.sagepub.com/home/jbx

Kerri J. Grove1, Viral Kansara2, Melissa Prentiss2, Debby Long2,
Muneto Mogi2, Sean Kim2, and Patrick J. Rudewicz1

Abstract
Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is becoming an important technology
to determine the distribution of drugs and their metabolites in the tissue of preclinical species after dosing. Interest in IMS
is growing in the ophthalmology field, but little work to this point has been done to investigate ocular drug transit using
this technology. Information on where and how a drug is distributing through the eye is important in understanding efficacy
and whether it is reaching the desired target tissue. For this study, ocular distribution of brimonidine was investigated in
rabbits following topical administration. Brimonidine has been shown to lower intraocular pressure and is approved to
treat glaucoma, the second leading cause of blindness in the world. We have developed IMS methods to assess transit of
topically administered brimonidine from the anterior to the posterior segment of rabbit eyes. Using IMS, brimonidine was
detected in the cornea, aqueous humor, iris, and posterior segments of the eye. The distribution of brimonidine suggests
that the route of transit following topical administration is mainly through the uvea-scleral route. This study demonstrates
that IMS can be applied to assess ocular transit and distribution of topically administered drugs.
Keywords
imaging mass spectrometry, ADME/PK, label-free technologies, mass spectrometry

Introduction
In drug discovery and development, matrix-assisted laser
desorption/ionization (MALDI) imaging mass spectrometry (IMS) is growing in importance as a technology for
determining the localization of drugs and their metabolites
in animal tissue after dosing. In this context, MALDI IMS
has been used to help answer questions of drug distribution,
concentration, metabolism, and toxicity.1-7 Unlike other
common analytical techniques used in drug discovery and
development for the determination of drug distribution such
as autoradiography, IMS has an advantage of not requiring
a label. IMS has also been gaining interest in the ophthalmology field, with studies designed to (1) assess the relative
distribution of endogenous molecules in various ocular anatomical structures, (2) determine posttranslational modifications of ocular proteins, and (3) examine the distribution
of exogenous compounds dosed in the eye.8-15 However,
little work to this point has been done to investigate ocular
drug transit using this technology.
In this study, we used MALDI IMS to examine the distribution of topically administered brimonidine, a drug used
to treat glaucoma. Glaucoma represents a group of diseases
that can cause damage to the optic nerve and, if left
untreated, ultimately result in vision loss and blindness. A

primary risk factor for glaucoma is increased intraocular
pressure, and as such, it is a major focus in the treatment of
glaucoma.16 Brimonidine is a selective α2-adrenergic receptor agonist that is used in the treatment of glaucoma as a
topical eye drop medication. It has been shown to reduce
intraocular pressure by both reducing aqueous humor production and increasing outflow through the trabecular
meshwork.17 Thus, by reducing pressure, it would have a
protective effect on retinal ganglion nerve cells.16 Indeed,
studies using 14C-brimonidine demonstrated that brimonidine reached posterior tissues of the eye at nanomolar concentrations after topical administration in preclinical
species.18
The eye is a complex organ that has many unique anatomical features. It contains two main divisions: the anterior
1

Novartis Institutes for BioMedical Research, Emeryville, CA, USA
Novartis Institutes for BioMedical Research, Cambridge, MA, USA

Received Mar 15, 2017, and in revised form Jul 16, 2017. Accepted for
publication Jul 17, 2017.
Corresponding Author:
Kerri Grove, Novartis Institutes for BioMedical Research, Global
Discovery Chemistry, 5300 Chiron Way, Emeryville, CA 94608, USA.
Email: kerri.grove@novartis.com

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Table of Contents for the Digital Edition of SLAS Discovery - Special Issue on Advances in MALDI Mass Spectrometry for Drug Discovery - Volume 22 Issue 10 - December 2017