title: Interactions between the dopamine agonist, bromocriptine and the efflux protein, P-glycoprotein at the blood-brain barrier in the mouse.
abstract: Bromocriptin (BCT) is a dopaminergic receptor agonist, poorly transported through the blood-brain barrier (BBB) and responsible for central side effects. Interactions between BCT and the efflux protein, P-glycoprotein (Pgp), have been described in vitro but nothing is known in vivo nor at the BBB level. At the BBB, in vivo, we investigated BCT as (i) a Pgp substrate by comparing the brain uptake in CF1 mdr1a(-/-) and mdr1a(+/+) mice with or without inhibitors of Pgp (valspodar, elacridar); (ii) a Pgp inducer by looking at the effect of repeated doses of BCT on cerebral uptake of digoxin and comparing it to the effect of dexamethasone and rifampicin; (iii) a Pgp inhibitor by determining the effect of a single dose of BCT on cerebral uptake of digoxin and comparing it to the effect of valspodar. CF1 mdr1a(-/-) mice showed much higher brain uptake of BCT than CF1 mdr1a(+/+) mice and brain uptake of BCT was higher in CF1 mdr1a(+/+) mice pre-treated with valspodar or elacridar indicating that BCT is a Pgp substrate at the BBB level. Brain uptake of digoxin was not modified in CF1 mdr1a(+/+) mice pre-treated with a single dose or repeated doses of BCT, indicating that BCT is neither a Pgp inductor nor a Pgp inhibitor at the BBB in the chosen experimental setting. In vivo, at the mouse BBB level and in our experimental conditions, bromocriptin is a Pgp substrate but is not a Pgp modulator.
authors.affiliation: EA 2706, Département de Pharmacie Clinique, Faculté de Pharmacie, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vautier
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Hélène
authors.initials: H
authors.lastname: Chacun
authors.forename: Véronique
authors.initials: V
authors.lastname: Picard
authors.forename: François
authors.initials: F
authors.lastname: Gimenez
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000166:Acridines / Q000008:administration & dosage; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001971:Bromocriptine / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000008:administration & dosage; D018491:Dopamine Agonists / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D003524:Cyclosporins; D018491:Dopamine Agonists; D044005:Tetrahydroisoquinolines; D001971:Bromocriptine; C095122:multidrug resistance protein 3; C083501:Elacridar; C070272:valspodar