Abstract
Lacosamide is a newer anticonvulsant and is the only one that enhances the slow inactivation of voltage gated sodium channels. It is also claimed to have disease-modifying potential, but its pharmacokinetic properties have been much less discussed in the literature. In rats, lacosamide shows restricted distribution to tissues, and the brain-to-plasma partition coefficient (Kp) is only 0.553. In this study, the brain disposition of lacosamide was evaluated in rat brains, and its neuropharmacokinetic parameters (i.e., protein binding and intracellular accumulation) were assessed using in vitro methods. Brain slice experiments and brain homogenate binding studies were performed for several drugs acting on the central nervous system, and drugs were assayed by using a liquid chromatography-mass spectrometry system. By applying a combined approach, it was found that (1) the unbound volume of distribution in the brain for lacosamide (Vu,brain = 1.37) was lower than that of other classical anticonvulsants; (2) the unbound fraction of lacosamide in the brain (0.899) was slightly lower than its unbound fraction in plasma (0.96); (3) the unbound intracellular-to-extracellular concentration ratio of lacosamide was 1.233, meaning that lacosamide was accumulated in the intracellular space because of its physicochemical properties and zwitterionic structure; and (4) the unbound brain-to-plasma concentration ratio of lacosamide was lower than the total brain-to-plasma concentration ratio (Kp,uu,brain = 0.42 vs. Kp = 0.553). In conclusion, the limited brain distribution of lacosamide is not related to its nonspecific protein-binding capacity; rather, an active transport mechanism across the blood–brain barrier may be involved, which reduces the anticonvulsant and/or antiepileptogenic actions of this drug.
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References
Becker S, Liu X (2006) Evaluation of the utility of brain slice methods to study brain penetration. Drug Metab Dispos 34:855–861
Behr C, Lévesque M, Ragsdale D, Avoli M (2015) Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy. Epilepsy Res 115:8–16
Beyreuther BK, Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T (2007) Lacosamide: a review of preclinical properties. CNS Drug Rev 13:21–42
Brandt C, Heile A, Potschka H, Stoehr T, Löscher W (2006) Effects of the novel antiepileptic drug lacosamide on the development of amygdala kindling in rats. Epilepsia 47:1803–1809
Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs JP, Gibbs MA, Hatch H, Hop CECA, Kasman IN, Laperle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, Van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165–174
Errington AC, Stohr T, Heers C, Lees G (2008) The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 73:157–169
Fisar Z, Krulik R, Fuksova K, Sikora J (1996) Imipramine distribution among red blood cells, plasma and brain tissue. Gen Physiol Biophys 15:51–64
Fridén M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2007) In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos 35:1711–1719
Fridén M, Ducrozet F, Middleton B, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2009) Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug Metab Dispos 37:1226–1233
Fridén M, Bergström F, Wan H, Rehngren M, Ahlin G, Hammarlund-Udenaes M, Bredberg U (2011) Measurement of unbound drug exposure in brain: modeling of pH partitioning explains diverging results between the brain slice and brain homogenate methods. Drug Metab Dispos 39:353–362
Funahashi T, Floyd RA, Carney JM (1994) Age effect on brain pH during ischemia/reperfusion and pH influence on peroxidation. Neurobiol Aging 15:161–167
Gáll Z, Vancea S, Szilágyi T, Gáll O, Kolcsár M (2015) Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats. Eur J Pharm Sci 68:106–113
Hammarlund-Udenaes M, Fridén M, Syvänen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25:1737–1750
Hammarlund-Udenaes M, Bredberg U, Fridén M (2009) Methodologies to assess brain drug delivery in lead optimization. Curr Top Med Chem 9:148–162
Kalvass JC, Maurer TS (2002) Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23:327–338
Koo T-S, Kim S-J, Ha D-J, Baek M, Moon H (2011) Pharmacokinetics, brain distribution, and plasma protein binding of the antiepileptic drug lacosamide in rats. Arch Pharm Res 34:2059–2064
Licko T, Seeger N, Zellinger C, Russmann V, Matagne A, Potschka H (2013) Lacosamide treatment following status epilepticus attenuates neuronal cell loss and alterations in hippocampal neurogenesis in a rat electrical status epilepticus model. Epilepsia 54:1176–1185
Liu X, Van Natta K, Yeo H, Vilenski O, Weller PE, Worboys PD, Monshouwer M (2009) Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos 37:787–793
Liu JYW, Thom M, Catarino CB, Martinian L, Figarella-Branger D, Bartolomei F, Koepp M, Sisodiya SM (2012) Neuropathology of the blood–brain barrier and pharmaco-resistance in human epilepsy. Brain 135:3115–3133
Loryan I, Fridén M, Hammarlund-Udenaes M (2013) The brain slice method for studying drug distribution in the CNS. Fluids Barriers CNS 10:6
Loryan I, Sinha V, Mackie C, Van Peer A, Drinkenburg W, Vermeulen A, Morrison D, Monshouwer M, Heald D, Hammarlund-Udenaes M (2014) Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery. Pharm Res 31:1–17
Loryan I, Sinha V, Mackie C, Van Peer A, Drinkenburg WH, Vermeulen A, Heald D, Hammarlund-Udenaes M, Wassvik CM (2015) Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates. Mol Pharm 12:520–532
Niespodziany I, Leclère N, Vandenplas C, Foerch P, Wolff C (2013) Comparative study of lacosamide and classical sodium channel blocking antiepileptic drugs on sodium channel slow inactivation. J Neurosci Res 91:436–443
Obach RS (1999) Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350–1359
Rogawski MA, Tofighy A, White HS, Matagne A, Wolff C (2015) Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res 110:189–205
Siqueira IR, Cimarosti H, Fochesatto C, Salbego C, Netto CA (2004) Age-related susceptibility to oxygen and glucose deprivation damage in rat hippocampal slices. Brain Res 1025:226–230
Wan H, Rehngren M, Giordanetto F, Bergström F, Tunek A (2007) High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery. J Med Chem 50:4606–4615
Wang Y, Welty DF (1996) The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res 13:398–403
Wang Y, Brittain JM, Jarecki BW, Park KD, Wilson SM, Wang B, Hale R, Meroueh SO, Cummins TR, Khanna R (2010) In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein-2 identifies a pocket important in modulating sodium channel slow inactivation. J Biol Chem 285:25296–25307
Zhang C, Chanteux H, Zuo Z, Kwan P, Baum L (2013) Potential role for human P-glycoprotein in the transport of lacosamide. Epilepsia 54:1154–1160
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Zsolt Gáll was supported by the Internal Grant for Scientific Research of University of Medicine and Pharmacy of Tîrgu Mureş, Romania (Contract No. 17800/11/22.12.2015).
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Gáll, Z., Vancea, S. Distribution of lacosamide in the rat brain assessed by in vitro slice technique. Arch. Pharm. Res. 41, 79–86 (2018). https://doi.org/10.1007/s12272-017-0966-2
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DOI: https://doi.org/10.1007/s12272-017-0966-2