BBB transport and P-glycoprotein functionality using MDR1A (-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123.
OBJECTIVE
The effect of P-glycoprotein (Pgp) on brain distribution using mdr1a (-/-) mice was investigated.


METHODS
Fluorescein (Flu) and FD-4 were used to check whether blood-brain barrier (BBB) integrity was maintained in mdr1a (-/-) mice. The Pgp substrate rhodamine-123 (R123) was infused and total brain, blood and brain microdialysate concentrations in mdr1a (-/-) mice and wild-type mice were compared.


RESULTS
Maintenance of BBB integrity was indicated by equal total brain/blood ratios of Flu and FD-4 in both mice types. R123 concentrations in brain after i.v. infusion were about 4-fold higher in mdr1a (-/-) than in wild-type mice (P < 0.05), without changes in blood levels. After microdialysis experiments the same results were found, excluding artifacts in the interpretation of Pgp functionality by the use of this technique. However the 4-fold ratio in brain was not reflected in corresponding microdialysates. No local differences of R123 in the brain were found. By the no-net-flux method in vivo recovery appeared to 4.6-fold lower in mdrla (-/-) mice compared with wild-type mice.


CONCLUSIONS
Pgp plays an important role in R123 distribution into the brain. Using intracerebral microdialysis, changes in in vivo recovery by the absence or inhibition of Pgp (or active efflux in general) need to be considered carefully.
de Lange
E C
EC
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, The Netherlands. L.Lange@LACDR.Leidenuniv.nl
de Bock
G
G
Schinkel
A H
AH
de Boer
A G
AG
Breimer
D D
DD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D019793:Fluorescein / Q000493:pharmacokinetics; D005456:Fluorescent Dyes; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017551:Microdialysis; D020112:Rhodamine 123 / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D019793:Fluorescein