G. Fricker et al
Octreotide transport across the blood brain barrier
1313
Our confocal images show that NBD-octreotide accumula-
tion in the lumens of porcine brain capillaries was reduced to
cellular levels or below by metabolic inhibition (NaCN),
unlabelled octreotide and by both p-glycoprotein and Mrp2
substrates, respectively. In contrast, neither octreotide nor the
p-glycoprotein and Mrp2 substrates had any eect on cellular
accumulation of NBD-octreotide. This suggests, that cellular
accumulation of the ¯uorescent octreotide derivative is not
carrier mediated, an observation that agrees with previous
studies on other somatostatin analogues (Banks et al., 1990;
Abbruscato et al., 1997). Consistent with the inhibition
pattern for NBD-octreotide transport, we found that
unlabelled octreotide was a potent inhibitor of luminal
accumulation of a p-glycoprotein substrate and an Mrp2
substrate. All of these ®ndings point to p-glycoprotein and
Mrp2 as the active components of the blood brain barrier
contributing to the low penetration of the somatostatin
derivative, octreotide, into the CNS. In this regard, in liver
and kidney, ABC-transporters also are responsible for the
active excretion of somatostatin analogues across the bile
canalicular membrane and proximal tubular brush border
membrane, respectively (Yamada et al., 1998; Gutmann et
al., 2000).
(Witt et al., 2000), cyclosporin A (Begley, 1992; Tsuji et al.,
1993) or some small model peptides between 2 and 3 amino
acids length (Chikhale et al., 1995). In addition, eux
transporters seem to be involved in brain to blood transport
of several peptides of neurologic relevance, like oxytocin
(Durham et al., 1991) or corticotropin releasing hormone
(Martins & Banks, 1996), although the molecular nature of
these transporters has not yet been clari®ed.
Taken together, all data suggest that ABC transporters
may have a more general function in clearing the CNS from
peptides. Our experiments together with the previous ®ndings
(Banks et al., 1990; 1994; Kitazawa et al., 1998) as well as
preliminary inhibition experiments with octreotide derivatives
(data not shown) argue that ABC transporters play a major
role in preventing somatostatin analogue peptides from entry
into the central nervous system. This may be of special
importance for the treatment of somatostatin sensitive brain
tumours and the interpretation of diagnostic somatostatin
receptor scans, when tumours are shielded by an intact blood
brain barrier.
ABC transporters also carry other peptides out of the
brain, such as Met-enkephalin analogue derivatives of d-
opioid receptor selective peptide D penicillamine (DPDPE)
This study was supported by the German Research Foundation
DFG-Grant FR1211/6-2, and a Grant of Baden-Wurttemberg's
È
Research Center Program: ABC-Proteins and Drug Transport.
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British Journal of Pharmacology vol 135 (5)