Page 14 - Shimadzu Journal vol.3 Issue3

Interview

us to see the distribution of each of the unaltered substances and
metabolites. Members of the safety research section in our company
have also said that they would like to use it to investigate toxicity
mechanisms. This is because toxicity is sometimes caused by
unaltered substances, and sometimes by metabolites.

substance will have risen compared with its state prior to
administration. If we administer a drug or a compound that is a
candidate for development, and the endogenous substance is Furthermore, it may be effective in the evaluation of safety
reduced, allowing recovery from the disorder, the fluctuation in said considering the difference between animal species. One example is a
endogenous substance indicates pathological improvement case where some data shows a particular toxicity present in rats,
indirectly. Additionally, if the phenomenon is caused by the which is caused by a metabolite that is only produced in rats, and
predicted efficacy mechanism of the development candidate therefore cannot be created in humans. Not only ARG but also mass
compound, analyzing the phenomenon demonstrates that the drug spectrometry offers visual information. If it is possible to demonstrate
has worked in line with its concept. Furthermore, if comprehensive that the toxicity is caused not by unaltered substance but rather by
analysis allows identification of types of endogenous substance, this metabolites that are specific to rats, we can consider that the toxicity
means it may in the future allow the discovery of biomarkers that are may not occur in humans.
clinically effective. This is an extremely attractive prospect.
That’s very interesting!
So you are talking not only about drug discovery that aims for a As I just said, the great advantage is that it can be used not only for
cure, but also going a little further to the diagnostic stage. Early compounds but also for evaluating biomarkers that are active at the
diagnosis and early cure are obviously important, but it is same time.
extremely interesting to hear how you are seeking biomarkers
useful for determining the effectiveness of prognosis.
The non-targeting approach? That’s a particular feature of this
method. How about any disadvantages?
Comparison with Autoradiography (ARG) There is no guarantee that all compounds being measured can be
ionized. That’s the main disadvantage. In contrast to marker analysis,
What are some of the conventional methods for evaluating
mass spectrometry can’t detect non-ionized compounds, so it’s not
tissue distribution? possible to use it to evaluate absolutely any and every compound.
In general, for a single project, a labeled compound is not
synthesized at the point at which there are still multiple candidate That’s true. That’s the reason whole-body ARG probably won’t
compounds. Unlabeled compounds are administered, and organs
be replaced completely with IMS, isn’t it? How about sensitivity?
subsequently removed, after which quantitative analysis is performed
using LCMS on the homogenate of those organs. This is a very general comment, but MALDI currently compares
poorly with LCMS and LC-MS/MS.
And do you use autoradiography (ARG) after that, as part of the
research process? We are pressing ahead with improvements to sensitivity in
pretreatment, thanks to Mitsubishi Tanabe Pharma’s cooperation.
Yes. As the research stage progresses and we narrow down the
compounds, we use radio-isotope (RI) labeled compounds to evaluate Yes, and then we need to think about what IMS is targeting, how
where a compound is distributed within the body after administration, much we can expect from it, and what it will be used for. If the
where it builds up, and how long it takes before it is excreted, with target compound is highly ionized, which allows evaluation of
the aim of applying for approval as a pharmaceutical product. effective dosage, then IMS can be used in efficacy mechanism
analysis. But if it’s not, then looking at efficacy evaluation levels
might be difficult. When evaluating toxicity mechanisms, however,
What are the advantages and disadvantages of IMS in
the dose and distribution quantity of the candidate compounds is
comparison with ARG?
sufficient, making their levels detectable. If IMS can be used for that
The advantages are, firstly and most importantly, that we can purpose, it will offer attractive evaluation methods.
perform evaluation at an early stage, prior to having to narrow the
compounds down to one. The second relates to the greatest attribute The microscopic level resolution is also part of the comparison
of the mass spectrometer. With ARG, it is not possible to distinguish
to ARG, isn’t it?
between the unaltered substance and metabolite distributions from
marker tissue distribution information. In particular, when there are Given the problem of ionization, it is difficult to imagine that IMS
multiple metabolites present, the distribution and buildup completely replaces ARG when considering the current quantitative
information obtained is for a mixture of behaviors, where we don’t ARG results. The iMScope TRIO performs best when it is used not to
know the ratio of the metabolites. Using a mass spectrometer allows evaluate whole-body distribution, but rather when it is focused on a

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