Interactions between riluzole and ABCG2/BCRP transporter

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood-brain barrier (BBB). Only riluzole is approved for ALS treatment. We have investigated riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (-/-) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (-/-) mice and BeWo cells showed a higher uptake of riluzole when pretreated with a BCRP inhibitor. After repeated doses of riluzole, BCRP activity was increased in CF1 mdr1a (-/-) mice, riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on riluzole and P-glycoprotein show that drug-drug interactions between riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS.

[1]  D. Cleveland.  From Charcot to SOD1 Mechanisms of Selective Motor Neuron Death in ALS , 1999, Neuron.

[2]  Qingcheng Mao,et al.  Role of the breast cancer resistance protein (ABCG2) in drug transport , 2005, The AAPS Journal.

[3]  M. Nedergaard,et al.  The blood–brain barrier: an overview Structure, regulation, and clinical implications , 2004, Neurobiology of Disease.

[4]  G. Fricker,et al.  Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. , 2004, Molecular pharmacology.

[5]  D. Greenblatt,et al.  Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in rats , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[6]  S. Cisternino,et al.  Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood-brain barrier. , 2004, Cancer research.

[7]  Masahiko Watanabe,et al.  Functional expression of rat ABCG2 on the luminal side of brain capillaries and its enhancement by astrocyte‐derived soluble factor(s) , 2004, Journal of neurochemistry.

[8]  J. Schuetz,et al.  The Stem Cell Marker Bcrp/ABCG2 Enhances Hypoxic Cell Survival through Interactions with Heme* , 2004, Journal of Biological Chemistry.

[9]  J. Julien,et al.  Amyotrophic Lateral Sclerosis Unfolding the Toxicity of the Misfolded , 2001, Cell.

[10]  J. Schellens,et al.  The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. , 2005, Cancer research.

[11]  R. Kim,et al.  Nuclear receptors and drug disposition gene regulation. , 2005, Journal of pharmaceutical sciences.

[12]  V. Meininger,et al.  Minocycline and riluzole brain disposition: interactions with p‐glycoprotein at the blood–brain barrier , 2007, Journal of neurochemistry.

[13]  Hong Zhang,et al.  The FASEB Journal express article 10.1096/fj.02-1131fje. Published online September 4, 2003. Expression and functional characterization of ABCG2 in brain endothelial cells and vessels , 2022 .

[14]  W. T. Beck,et al.  Identification of a Novel Estrogen Response Element in the Breast Cancer Resistance Protein (ABCG2) Gene , 2004, Cancer Research.

[15]  M. Nishiyama,et al.  Pharmacological effects of the tremorgenic mycotoxin fumitremorgin A. , 1986, Japanese journal of pharmacology.

[16]  W. Pardridge,et al.  Capillary Depletion Method for Quantification of Blood–Brain Barrier Transport of Circulating Peptides and Plasma Proteins , 1990, Journal of neurochemistry.

[17]  Atsushi Ose,et al.  Quantitative Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Limiting Brain and Testis Penetration of Xenobiotic Compounds , 2008, Drug Metabolism and Disposition.

[18]  Alfred H. Schinkel,et al.  BREAST CANCER RESISTANCE PROTEIN (BCRP/ABCG2) TRANSPORTS FLUOROQUINOLONE ANTIBIOTICS AND AFFECTS THEIR ORAL AVAILABILITY, PHARMACOKINETICS, AND MILK SECRETION , 2006, Drug Metabolism and Disposition.

[19]  P. Leigh,et al.  Dose-ranging study of riluzole in amyotrophic lateral sclerosis , 1996, The Lancet.

[20]  V. Meininger,et al.  A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. , 1994, The New England journal of medicine.

[21]  A. Schinkel,et al.  Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. , 2003, Advanced drug delivery reviews.

[22]  Alfred H. Schinkel,et al.  Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine , 2005, Journal of Pharmacology and Experimental Therapeutics.

[23]  J. Unadkat,et al.  Hormonal Regulation of BCRP Expression in Human Placental BeWo Cells , 2008, Pharmaceutical Research.

[24]  P. Leung,et al.  Progesterone Receptor (PR) Isoforms PRA and PRB Differentially Regulate Expression of the Breast Cancer Resistance Protein in Human Placental Choriocarcinoma BeWo Cells , 2008, Molecular Pharmacology.

[25]  J. Schellens,et al.  Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  K. Brouwer,et al.  Increased brain P-glycoprotein in morphine tolerant rats. , 1999, Life sciences.

[27]  M. Leggas,et al.  Progesterone Acts via Progesterone Receptors A and B to Regulate Breast Cancer Resistance Protein Expression , 2008, Molecular Pharmacology.

[28]  K. Iseki,et al.  Effects of sex hormones on regulation of ABCG2 expression in the placental cell line BeWo. , 2006, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[29]  P. Mark,et al.  P-glycoprotein restricts access of cortisol and dexamethasone to the glucocorticoid receptor in placental BeWo cells. , 2006, Endocrinology.

[30]  L. Doyle,et al.  Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. , 2000, Cancer research.

[31]  Christopher M Waters,et al.  Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. , 2008, American journal of physiology. Cell physiology.