Use of Verapamil as a Potential P-Glycoprotein Inhibitor in a Patient with Refractory Epilepsy

Abstract

Spanish

French

OBJECTIVE

To describe a patient in whom we used adjunctive verapamil therapy was used for its P-glycoprotein inhibitory effects.

CASE SUMMARY

Verapamil was added to the antiepileptic drug regimen of a 24-year-old woman with intractable epilepsy. The average time interval between hospitalizations for complex partial status doubled. The addition of verapamil greatly improved overall seizure control and subjective quality of life in this pharmacoresistant patient.

DISCUSSION

The overexpression of P-glycoprotein in the central nervous system may be one mechanism of pharmacoresistance in patients with epilepsy. The calcium-channel blocker verapamil is a known inhibitor of P-glycoprotein and may function to block P-glycoprotein—modulated efflux of antiepileptic drugs in the brain, thereby raising the intracellular concentration of antiepileptic drugs and ultimately decreasing seizure burden in patients with refractory epilepsy.

CONCLUSIONS

Verapamil may offer pharmacoresistant patients hope of improved seizure control due to its potential P-glycoprotein inhibitory effects.

Keywords

antiepileptic drugs epilepsy P-glycoprotein verapamil

Get full access to this article

View all access options for this article.

References

1. Tishler

Weinberg

Hinton

Barbaro

Annett

Raffel

MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 1995;36:1–6.

2. Dombrowski

Desai

Marroni

Cucullo

Goodrich

Bingaman

Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 2001;42: 1501–6.

3. Siddiqui

Kerb

Weale

Brinkmann

Smith

Goldstein

Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003;348:1442–8.

4. Potschka

Fedrowitz

Loscher

P-glycoprotein—mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood—brain barrier: evidence from microdialysis experiments in rats. Neurosci Lett 2002;327:173–6.

5. Potschka

Fedrowitz

Loscher

P-glycoprotein and multidrug resistance—associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001;12:3557–60.

6. Rizzi

Caccia

Guiso

Richichi

Gorter

Aronica

Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance. J Neurosci 2002;22:5833–9.

7. Loscher

Potschka

Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther 2002;301:7–14.

8. Potschka

Loscher

In vivo evidence for p-glycoprotein—mediated transport of phenytoin at the blood—brain barrier of rats. Epilepsia 2001;42:1231–40.

9. MacPhee

McInnes

Thompson

Brodie

Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction. Lancet 1986;1: 700–3.

10.

10. Beattie

Biller

Mehlhaus

Murray

Verapamil-induced carbamazepine neurotoxicity. A report of two cases. Eur Neurol 1988;28:104–5.

11.

11. Bahls

Ozuna

Ritchie

Interactions between calcium channel blockers and the anticonvulsants carbamazepine and phenytoin. Neurology 1991;41:740–2.

12.

12. Straub

Kohling

Speckmann

Strychnine-induced epileptiform activity in hippocampal and neocortical slice preparations: suppression by the organic calcium antagonists verapamil and flunarizine. Brain Res 1997;773:173–80.

13.

13. Straub

Kohling

Lucke

Fauteck

Speckmann

Moskopp

The effects of verapamil and flunarizine on epileptiform activity induced by bicuculline and low Mg+2 in neocortical tissue of epileptic and primary non-epileptic patients. Brain Res 1996;733:307–11.

14.

14. Wurpel

Iyer

SN.

Calcium channel blockers verapamil and nimodipine inhibit kindling in adult and immature rats. Epilepsia 1994;35:443–9.

15.

15. Chaisewikul

Baillie

Marson

AG.

Calcium antagonists as an addon therapy for drug-resistant epilepsy. Cochrane Database Syst Rev 2001;(4):CD002750.

16.

16. Oza

Clinical development of P glycoprotein modulators in oncology. In: Mechanisms of drug resistance in epilepsy: lessons from oncology. West Sussex, England: John Wiley & Sons, 2002:108.

17.

17. Owen

Pirmohamed

Tettey

Morgan

Chadwick

Park

BK.

Carbamazepine is not a substrate for P-glycoprotein. Br J Clin Pharmacol 2001;51:345–9.

18.

18. Sills

Kwan

Butler

DeLange

Van der Berg

Brodie

P-glycoprotein—mediated efflux of anti-epileptic drugs; preliminary studies in mdr1a knockout mice. Epilepsy Behav 2002;3:427–32.