In Vivo Monitoring and Pharmacokinetics of Valproic Acid in Breath

This assignment presents a study published in Chemical Communications, exploring the real-time, in vivo monitoring and pharmacokinetics of valproic acid (VPA) using exhaled breath analysis. The research utilizes EESI-MS (Electrospray ionization-mass spectrometry) to detect VPA biomarkers in breath, offering a non-invasive and pain-free method for establishing pharmacokinetic parameters and active drug concentrations. The methodology involves analyzing breath fingerprints of volunteers, both at a daily dose of valproic acid and without ingestion, to establish the presence and clearance of the drug. The study demonstrates a correlation between the signal strength of VPA markers in exhaled breath and the calculated free VPA fraction in blood, suggesting a potential for personalized prescription treatments. The findings highlight the potential of EESI-MS for clinical diagnostics, forensic investigations, and metabolomics, offering a significant step towards non-invasive drug monitoring.

RESEARCH POSTER PRESENTATION DESIGN © 2015
www.PosterPresentations.com
The exhaled breath tests have gained
significant attention and are an interesting
alternative to blood sampling: if there is an
appropriate device available, no medical
personnel is needed or hazardous waste can
be produced. Breath is still quite a simplified
matrix than plasma even though its chemical
composition is fundamentally complex. Given
these benefits only a few breath-based
approaches found an audience in clinical or
forensic research to diagnose, for example.
Pylori infection or extent of intoxication with
the alcohol.
Introduction
Due to the simulation of gamma-amino-
butyric-acid characteristic pathways and/or
sodium / calcium channels, valproic acid has
long been used for the treatment of epilepsy
and other neuropsychiatric illnesses. Several
factors, namely the protein binding potential
of VPA, which is both dependent on the
concentration of VPA and on the serum
albumin concentration, affected the
pharmacologically important free vPA
fraction.
Assay Using Valporic Acid (VPA, 2-
propylpentanoic acid, MW 14 4.21 g
mol1)
In this case, using EESI-MS (positive ion mode) for intake and
clearance control of VPA by evaluating the respirator from an ESI
source of the commercial quadrupole time-of-flight mass spectrometer.
This approach allows to establish pharmacokinetic (PK) parameters
and active drug concentration in real time without the need for sample
storage or pretreatment in a fast, non-Invasive and pain-free way.
Methodology
The volunteer's breath
fingerprints are given at a daily
dose of valproic acid (A), and the
average stable volunteer without
ingestion of valproic acid (B). Take
note of the severity gap. The
fragment in (A) demonstrates the
tandem MS fragmentation
sequence, with a NH3 loss of a
fragment at m / z= 160, a fraction
at m / z 125, and a corresponding
CO loss at m / z 97, the fragment
at m / z 97. A fragment at m / z 55
that could lead to C4H7 was also
found. Refer to the article for MS
details with high resolution
Analysis
Results
(top) Varies the signal of the breath
exhaled VPA markers at m / z= 143,
depending on the time spent
volunteering on 4 Depakines Chrono
500 tablets (m) and volunteers taking
each dose of 2 tablets (K). The
reduction is followed up by the
kinetics of first order with a half-life
of 9.24hours in the single dose
experiment 20 hours after ingestion
(when the body is no longer
increasing in concentration). (bottom)
Signal strength association at m / z=
143 with blood calculated free VPA
fraction. The dotted lines show 95
percent confidence bands of y=
7,7601x 1 (R2= 0,89) around the
linear suit.
Conclusion
We showed that pharmacokinetic valproic acid and human intake can
be tracked in the exhaled breath through a novel biomarker. Clear,
non-invasive, trauma-free and an important step to personalized
prescription treatment is the EESI-MS technique. This research is just
an early example of how EESI-MS could be used in vivo to control
drug metabolism. It has great scope for clinical diagnostics, forensic
investigation and metabolomics.
References
1. G. Peng, U. Tisch, O. Adams, M. Hakim, N. Shehada, Y. Y. Broza, S. Billan, R.
Abdah-Bortnyak, A. Kuten and H. Haick, Nat. Nanotechnol., 2009, 4, 669–673.
2. B. E. Dunn, H. Cohen and M. J. Blaser, Clin. Microbiol. Rev., 1997, 10, 720–741
3. Valproinsa¨ure. Pharmacologie, Klinischer Einsatz, Nebenwirkungen und
Therapierichtlinien., ed. G. Kra¨mer and J. Walden, SpringerVerlag, Berlin, 2002
Gerardo Gamez,zy a Liang Zhu,y a Andreas Disko,b Huanwen Chen,c Vladimir Azov,d Konstantin Chingin,a Gu¨nter Kra¨merb and Renato Zenobi*a
Received 18th January 2011, Accepted 10th February 2011 DOI: 10.1039/c1cc10343a
Real-time, in vivo monitoring and pharmacokinetics of valproic acid via a novel biomarker in exhaled breath