Abstract
The blood–brain barrier plays a vital role in the protection of the central nervous system. It is composed of endothelial cells with tight-junctions to limit the penetration of many endogenous and exogenous compounds, particularly hydrophilic xenobiotics. Nerve agents and pesticides are groups of compounds with high penetration potential into the central nervous system. However, oxime type antidotes are known to penetrate blood–brain barrier only in low concentration. The aim of presented study is to describe the pharmacokinetic profile of oxime K027 a novel antidote candidate. The main focus is on penetration of tested substance into the selected brain regions following time-dependent manner. The maximum concentration of the oxime K027 was attaining 15 and 30 min after i.m. application in plasma and brain tissue, respectively. The perfused brain tissue concentration was relatively high (10−7 M order of magnitude) and depending on the brain region it was constant 15–60 min after application. The highest concentration was found in the frontal cortex 15 min after application while the lowest measured concentration was determined in the basal ganglia. This study showed that oxime K027 is able to achieve high concentration level in perfused brain tissue relatively quickly, but also demonstrated rapid clearance from the central nervous system. These results are probably due to low overall uptake of oxime K027 into the brain.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amourette Ch, Lamproglou I, Barbier L, Fauquette W, Zoppe A, Viret R, Diserbo M (2009) Gulf war illness: effect of repeated stress and pyridostigmine treatment on blood–brain barrier permeability and cholinesterase activity in rat brain. Neurobehav Brain Res 203:207–214
Bajgar J, Hajek P, Slizova D, Krs O, Fusek J, Kuca K, Jun D, Bartosova L, Blaha V (2007) Changes of acetylcholinesterase activity in different brain areas following intoxication with nerve agents: biochemical and histochemical study. Chem Biol Interact 165:14–21
Bajgar J, Fusek J, Kassa J, Jun D, Kuca K, Hajek P (2008) An attempt to assess functionally minimal acetylcholinesterase aktivity necessary for survival of rats intoxicated with nerve agents. Chem Biol Interact 175:281–285
Bajgar J, Karasova JZ, Kassa J, Cabal J, Fusek J, Blaha V, Tesarova S (2010) Tabun-inhibited rat tissue and blood cholinesterases and their reactivation with the combination of trimedoxime and HI-6. Chem Biol Interact 187:287–290
Feng RM (2002) Assessment of blood–brain barrier penetration: in silico, in vitro and in vivo. Curr Drug Metab 3:647–657
Garcia GE, Campbell AJ, Olson J, Moorad-Doctor D, Morthole VI (2010) Novel oximes as blood–brain barrier penetrating cholinesterase reactivators. Chem Biol Interact 187:199–206
Gyenge M, Kalász H, Petroianu GA, Laufer R, Kuca K, Tekes K (2007) Measurement of K-27, an oxime-type cholinesterase reactivator by high-performance liquid chromatography with electrochemical detection from biological samples. J Chromatogr A 1161:146–151
Joosen MJA, Wortelboer HM, van Helden HPM (2011) Increasing oxime efficacy in the brain by blood–brain barrier modulation. In: 13th medical chemical defense conference 2011 abstract book, Munich, Germany, p 21
Kalász H, Laufer R, Szegi P, Kuca K, Musilek K, Tekes K (2008) HPLC study of the pharmacokinetics of K203. Acta Chromatogr 20:575–584
Karasova JZ, Kassa J, Pohanka M, Musilek K, Kuca K (2010) Potency of HI-6 to reactivate cyclosarin, soman and tabun inhibited acetylcholinesterase—in vivo study. Lett Drug Des Discov 7:516–520
Karasova JZ, Zemek F, Bajgar J, Vasatova M, Prochazka P, Novotny L, Kuca K (2011) Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain. J Pharmaceut Biomed 54:1082–1887
Karasova JZ, Chladek J, Hroch M, Fusek J, Hnidkova D, Kuca K (2012) Pharmacokinetics study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma. J Appl Toxicol. doi:10.1002/jat1699
Kassa J, Kuca K, Karasova JZ, Musilek K (2008) The development of new oximes and the evaluation of thein reactivating, therapeutic and neuroprotective efficacy against tabun. Mini-Rev Med Chem 8:1134–1143
Kassa J, Karasova JZ, Caisberger F, Musilek K, Kuca K, Jung Y-S (2010) A comparison of reactivating and therapeutic efficacy of the oxime K203 and its fluorinated analog (KR-22836) with currently available oximes (obidoxime, trimedoxime, HI-6) against tabun in rats and mice. J Enzym Inhib Med Chem 25:480–484
Kuca K, Bielavsky J, Cabal J, Kassa J (2003) Synthesis of new reactivator of tabun-inhibited acetylcholinesterase. Bioorg Med Chem Lett 13:3545–3547
Kuca K, Musilek K, Jun D, Pohanka M, Ghosh KK, Hrabinova M (2010) Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase. J Enzym Inhib Med Chem 25:509–512
Leeson PD, Davis AM (2004) Tine-related differences in the physical property profiles of oral drugs. J Med Chem 47:6338–6348
Lorke DE, Kalasz H, Petroianu GA, Tekesz K (2008) Entry of oximes into the brain: a review. Curr Med Chem 15:743–753
Löscher W, Potschka H (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76:22–76
Ohtsuki S, Terasaki T (2007) Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24:1745–1758
Pardridge WM (2007) Brain drug development and brain drug targeting. Pharm Res 24:1729–1732
Petroianu GA, Lorke DE, Hasan MY, Adem A, Sheen R, Nurulain SM, Kalasz H (2007a) Paraoxon has only a minimal effect on pralidoxime brain concentration in rats. J Appl Toxicol 27:350–357
Petroianu GA, Hasan MY, Nurulain SM, Nagelkerke N, Kassa J (2007b) New K-Oximes (K-27 and K-48) in comparison with Obidoxime (LuH-6), HI-6, trimedoxime (TMB-4), and pralidoxime (2-PAM): survival in rats exposed IP to the organophosphate paraoxon. Toxicol Mech Method 17:401–408
Pohanka M, Novotny L, Misik J, Kuca K, Karasova JZ, Hrabinova M (2009) Evaluation of cholinesterase activities dutiny in vivo intoxication using an electrochemical sensor strip—correlation with intoxication symptoms. Senzors 9:3627–3634
Sakurada K, Matsubara K, Shimizu K, Shiono H, Seto Y, Teute K, Toshibo M, Sakai I, Mukoyama H, Takatori T (2003) Pralidoxime iodide (2-PAM) penetrates across the blood–brain barrier. Neurochem Res 28:1401–1407
Terasaki T, Hosoya K (1999) The blood–brain barrier efflux transporters as a detoxifying system for the brain. Adv Drug Deliv Rev 36:195–209
Ueno M, Nakagawa T, Wu B, Onodera M, Juany CI, Kusaka T, Araki N, Sakamoto H (2010) Transporters in the brain endothelial barrier. Curr Med Chem 17:1125–1138
Voicu V, Sora I, Sarbu C, David V, Medvedovici A (2010) Hydrophobicity/hydrophilicity descriptors obtained from extrapolated chromatographic retention data as modelling tools for biological distribution: application to some oxime type acetylcholinesterase reactivators. J Pharm Biomed Anal 52:508–516
Acknowledgments
This study was supported by the Grant Agency of the Ministry of Education, Youth and Sports of the Czech Republic (No. ME09086).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Karasova, J.Z., Zemek, F., Musilek, K. et al. Time-Dependent Changes of Oxime K027 Concentrations in Different Parts of Rat Central Nervous System. Neurotox Res 23, 63–68 (2013). https://doi.org/10.1007/s12640-012-9329-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-012-9329-4