- Email: [email protected]
Hypothesis: An important role for R-verapamil in pharmacoresistant epilepsy
Bioscience Hypotheses (2009) 2, 52e53 available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
SHORT COMMUNICATION
Hypothesis: An important role for R-verapamil in pharmacoresistant epilepsy K. Hassanzadeh*, H. Ghavimi Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University (Medical Sciences), Tabriz, East Azarbaijan 51667-14776, Iran Received 25 September 2008; received in revised form 18 October 2008; accepted 23 October 2008
KEYWORDS R-verapamil; Pharmacoresistant epilepsy; P-glycoproteins
Abstract Drugs that block P-glycoprotein-modulated efflux of antiepileptic drugs in the brain, lead to increase their intracellular concentration. Addition of R-verapamil as one enantiomer of verapamil to antiepileptic drugs may facilitate the penetration of drugs to the brain and prevents their efflux from CNS without serious cardiovascular side effects. ª 2008 Elsevier Ltd. All rights reserved.
About 30% of epileptic patients do not respond to the usual antiepileptic drugs (AEDs), representing a major health problem associated with increased morbidity and mortality [1]. There is accumulating evidence demonstrating that multidrug transporters such as P-glycoprotein (PGP) and members of the multidrug resistance-associated protein (MRP) family are over-expressed in capillary endothelial cells and astrocytes in epileptogenic brain tissue, resulting in impaired AEDs access to the site of action. PGP and MRPs in the BBB are thought to act as an active defense mechanism, restricting the penetration of lipophilic substances into the brain. A large variety of compounds, including many lipophilic drugs, are substrates for either PGP or MRPs or both [2]. Drugs that block P-glycoproteinmodulated efflux of AEDs in the brain, lead to raise the intracellular concentration of AEDs and ultimately * Corresponding author. Tel.: þ98 914 415 6941; fax: þ98 411 334 4798. E-mail address: [email protected] (K. Hassanzadeh).
decrease seizure burden in patients with pharmacoresistant epilepsy. The calcium-channel blocker (ccb) verapamil is known as a good substrate for PGP [3,4]. It is reported that intravesical instillation chemotherapy with verapamil plus doxorubicin showed a significantly greater benefit than doxorubicin alone [5]. Verapamil is a racemate (R,S-verapamil) and previous studies have shown that R-verapamil is 8e10 times less potent than S-verapamil in its effect on cardiac conduction and prolongation of PR interval [6]. Earlier studies demonstrated that R-verapamil is more appropriate than racemic verapamil because relatively high plasma total drug concentrations can be achieved, without serious cardiovascular side effects [7]. Of related interest, there is no apparent difference in the inhibitory effects of either verapamil enantiomers for P-glycoprotein [7]. Previous studies have shown that R-verapamil at 225 mg/m2 orally every 4 h can be given safely in chemotherapy and is associated with serum levels considered active for PGP inhibition [8].
1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.10.006
An important role for R-verapamil in pharmacoresistant epilepsy Thus, according to the above information it is concluded that R-verapamil, the less cardiotoxic stereoisomer, may be sufficient to inhibit PGP-mediated transport in humans and cause to increase significantly the concentration of AEDs in the extracellular fluid of the cerebral cortex. Addition of Rverapamil to AEDs may facilitate the penetration of drugs to the brain and prevents their efflux from the central nervous system. In order to clarify the exact effects, basic and clinical researches on the interaction between R-verapamil and epilepsy are necessary.
References [1] Weiss J, Kerpen CJ, Lindenmaier H, Dormann SMG, Haefeli WE. Interaction of antiepileptic drugs with human P-glycoprotein in vitro. J Pharmacol Exp Ther 2003;307:262e7. [2] Wolfgang L, Heidrun P. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther 2002;301:7e14.
53
[3] Varma MVS, Ashokra Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 2003;48:347e59. [4] Potschka H, Baltes S, Lo ¨scher W. Inhibition of multidrug transporters by verapamil or probenecid does not alter bloode brain barrier penetration of levetiracetam in rats. Epilepsy Res 2004;58:85e91. [5] Kamimoto Y, Gatmaitan Z, Hsu J, Arias IM. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J Biol Chem 1989;264:11693e8. [6] Ahmed JH, Godden J, Meredith PA, Eliott HL. R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate. Br J Clin Pharmacol 1993;36:93e8. [7] Perrotton T, Trompier D, Chang XB, Di Pietro A, BaubichonCortay H. R- and S-verapamil differentially modulate the multidrug resistance protein MRP1. J Biol Chem 2007;282: 31542e8. [8] Tolcher AW, Cowan KH, Solomon D, Ognibene F, Goldspiel B, Chang R, et al. Phase I crossover study of paclitaxel with R-verapamil in patients with metastatic breast cancer. J Clin Oncol 1996;14:1173e84.
journal homepage: www.elsevier.com/locate/bihy
SHORT COMMUNICATION
Hypothesis: An important role for R-verapamil in pharmacoresistant epilepsy K. Hassanzadeh*, H. Ghavimi Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University (Medical Sciences), Tabriz, East Azarbaijan 51667-14776, Iran Received 25 September 2008; received in revised form 18 October 2008; accepted 23 October 2008
KEYWORDS R-verapamil; Pharmacoresistant epilepsy; P-glycoproteins
Abstract Drugs that block P-glycoprotein-modulated efflux of antiepileptic drugs in the brain, lead to increase their intracellular concentration. Addition of R-verapamil as one enantiomer of verapamil to antiepileptic drugs may facilitate the penetration of drugs to the brain and prevents their efflux from CNS without serious cardiovascular side effects. ª 2008 Elsevier Ltd. All rights reserved.
About 30% of epileptic patients do not respond to the usual antiepileptic drugs (AEDs), representing a major health problem associated with increased morbidity and mortality [1]. There is accumulating evidence demonstrating that multidrug transporters such as P-glycoprotein (PGP) and members of the multidrug resistance-associated protein (MRP) family are over-expressed in capillary endothelial cells and astrocytes in epileptogenic brain tissue, resulting in impaired AEDs access to the site of action. PGP and MRPs in the BBB are thought to act as an active defense mechanism, restricting the penetration of lipophilic substances into the brain. A large variety of compounds, including many lipophilic drugs, are substrates for either PGP or MRPs or both [2]. Drugs that block P-glycoproteinmodulated efflux of AEDs in the brain, lead to raise the intracellular concentration of AEDs and ultimately * Corresponding author. Tel.: þ98 914 415 6941; fax: þ98 411 334 4798. E-mail address: [email protected] (K. Hassanzadeh).
decrease seizure burden in patients with pharmacoresistant epilepsy. The calcium-channel blocker (ccb) verapamil is known as a good substrate for PGP [3,4]. It is reported that intravesical instillation chemotherapy with verapamil plus doxorubicin showed a significantly greater benefit than doxorubicin alone [5]. Verapamil is a racemate (R,S-verapamil) and previous studies have shown that R-verapamil is 8e10 times less potent than S-verapamil in its effect on cardiac conduction and prolongation of PR interval [6]. Earlier studies demonstrated that R-verapamil is more appropriate than racemic verapamil because relatively high plasma total drug concentrations can be achieved, without serious cardiovascular side effects [7]. Of related interest, there is no apparent difference in the inhibitory effects of either verapamil enantiomers for P-glycoprotein [7]. Previous studies have shown that R-verapamil at 225 mg/m2 orally every 4 h can be given safely in chemotherapy and is associated with serum levels considered active for PGP inhibition [8].
1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.10.006
An important role for R-verapamil in pharmacoresistant epilepsy Thus, according to the above information it is concluded that R-verapamil, the less cardiotoxic stereoisomer, may be sufficient to inhibit PGP-mediated transport in humans and cause to increase significantly the concentration of AEDs in the extracellular fluid of the cerebral cortex. Addition of Rverapamil to AEDs may facilitate the penetration of drugs to the brain and prevents their efflux from the central nervous system. In order to clarify the exact effects, basic and clinical researches on the interaction between R-verapamil and epilepsy are necessary.
References [1] Weiss J, Kerpen CJ, Lindenmaier H, Dormann SMG, Haefeli WE. Interaction of antiepileptic drugs with human P-glycoprotein in vitro. J Pharmacol Exp Ther 2003;307:262e7. [2] Wolfgang L, Heidrun P. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther 2002;301:7e14.
53
[3] Varma MVS, Ashokra Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 2003;48:347e59. [4] Potschka H, Baltes S, Lo ¨scher W. Inhibition of multidrug transporters by verapamil or probenecid does not alter bloode brain barrier penetration of levetiracetam in rats. Epilepsy Res 2004;58:85e91. [5] Kamimoto Y, Gatmaitan Z, Hsu J, Arias IM. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J Biol Chem 1989;264:11693e8. [6] Ahmed JH, Godden J, Meredith PA, Eliott HL. R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate. Br J Clin Pharmacol 1993;36:93e8. [7] Perrotton T, Trompier D, Chang XB, Di Pietro A, BaubichonCortay H. R- and S-verapamil differentially modulate the multidrug resistance protein MRP1. J Biol Chem 2007;282: 31542e8. [8] Tolcher AW, Cowan KH, Solomon D, Ognibene F, Goldspiel B, Chang R, et al. Phase I crossover study of paclitaxel with R-verapamil in patients with metastatic breast cancer. J Clin Oncol 1996;14:1173e84.