Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans.
OBJECTIVE
Single nucleotide polymorphisms in the human multidrug-resistance gene ABCB1 have been reported to be associated with altered expression and function of P-glycoprotein, an efflux transporter, expressed at the blood-brain barrier. To test whether certain ABCB1 haplotypes contribute to interindividual differences in central nervous system drug distribution, brain distribution of a model P-glycoprotein substrate, the calcium channel inhibitor verapamil, was measured by positron emission tomography (PET) in 2 groups of healthy volunteers.


METHODS
Ten homozygous carriers (cases) of the TTT haplotype (3435T, 1236T, and 2677T) and 10 controls homozygous for the wild-type CGC haplotype (3435C, 2677G, and 1236C) were administered a mean intravenous bolus of 412 +/- 114 MBq carbon 11-labeled verapamil containing less than 15 nmol of unlabeled verapamil. PET imaging of brain tissue and venous blood sampling were performed for 1 hour after dosing.


RESULTS
As a measure of brain penetration, the ratio of PET area under the time-radioactivity curve (AUC) to plasma AUC was calculated from time-radioactivity curves, with a mean ratio of 1.1 +/- 0.3 (SD) (95% confidence interval, 0.9-1.3) for cases and 1.1 +/- 0.2 (95% confidence interval, 0.9-1.2) for controls, respectively (P = .96). Mean brain AUC values were 31.2 +/- 3.9 and 35.7 +/- 5.7 for the TTT and CGC haplotype, respectively (P = .11). Plasma AUCs were not significantly different.


CONCLUSIONS
No difference in the brain distribution of [(11)C]verapamil could be detected in healthy volunteers differing in ABCB1 haplotypes.
Brunner
Martin
M
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Institute of Medical and Chemical Laboratory Diagnostics, Vienna, Austria. marin.brunner@meduniwien.ac.at
Langer
Oliver
O
Sunder-Plassmann
Raute
R
Dobrozemsky
Georg
G
Müller
Ulrich
U
Wadsak
Wolfgang
W
Krcal
Andreas
A
Karch
Rudolf
R
Mannhalter
Christine
C
Dudczak
Robert
R
Kletter
Kurt
K
Steiner
Ilka
I
Baumgartner
Christoph
C
Müller
Markus
M
D000328:Adult; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002490:Central Nervous System / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D019450:Genes, MDR; D006239:Haplotypes; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D049268:Positron-Emission Tomography; D014018:Tissue Distribution; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics*
D002250:Carbon Radioisotopes; D002491:Central Nervous System Agents; D014700:Verapamil