Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development.
We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.
Marchi
Nicola
N
Dept Neuroscience, Mario Negri Inst for Pharmacol Res, Via Eritrea 62, 20157 Milano, Italy.
Guiso
Giovanna
G
Caccia
Silvio
S
Rizzi
Massimo
M
Gagliardi
Barbara
B
Noé
Francesco
F
Ravizza
Teresa
T
Bassanini
Stefania
S
Chimenti
Stefano
S
Battaglia
Giorgio
G
Vezzani
Annamaria
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000002:abnormalities / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002828:Choristoma / Q000139:chemically induced; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006624:Hippocampus; D008297:Male; D016555:Matched-Pair Analysis; D008746:Methylazoxymethanol Acetate; D017294:Ondansetron / Q000493:pharmacokinetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D012709:Serum Albumin / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D012333:RNA, Messenger; D012709:Serum Albumin; D017294:Ondansetron; D008746:Methylazoxymethanol Acetate