acids (Fo ̈ger et al. 2006 ). Examples of nutrient-based compounds that interact with
P-gp and other ABC transporters are Vitamin E TPGS (tocopheryl polyethylene
glycol succinate) (Collnot et al. 2006 ) and flavonoids (Brand et al. 2006 ). While
there is no clinical evidence to date that any food components or nutraceuticals used
in veterinary species impact on drug safety at the level ofP-gp (or indeed cyto-
chrome P450), the human experience of toxic interactions between grapefruit juice
and St John’s wort andimportantdrugs leaves no room for complacency (Holtzman
et al 2006 ). Awareness of potential interactions in breeds and species with differ-
entialP-gp expression and increasing knowledge of inter-species differences in
transporter expression and distribution will inform improved dosing regimens and
enhance understanding of inherent risks in cases of polypharmacy.
Other ABC transporters, including MDR resistance associated proteins (MRPs)
and breast cancer resistant protein (BCRP), are also being investigated for their
potential importance in drug disposition in veterinary medicine. MRP1 (ABCC1),
MRP2 (ABCC2) and BCRP (ABCG2) may be present to varying extents and impact
on the BBB, bile duct and mammary glands of several species (Alvarez et al. 2006 ).
Important discoveries were that fluoroquinolone secretion into milk was mediated
byAbcg2in wild-type but not Abcg2 (/) mice (Merino et al. 2006 ), and the
corollary thatABCG2 expression is up-regulated in the mammary glands of lactat-
ing sheep (Pulido et al. 2006 ). Knowledge of the existence and functions of such
transport pathways for drugs to distribute into milk could lead to strategies to
manipulate residue depletion rates. In relation to MRPs, there is evidence that
ABCC1 is present on canine lymphocytes and that, in association with ABCB1, it
may play a role in resistance to chemotherapeutic agents (Schleis et al. 2008 ).
Whether ABCC1 has any practical significance for disposition of, for example,
ivermectin is questionable. While ivermectin interacts with ABCC1, ABCC2 and
ABCC3 in vitro, albeit with low affinity (Lespine et al. 2008 ), these effects do not
seem to be pharmacologically relevant in the presence of a background
P-gp-mediated efflux in MDR1- and MRP-transfected epithelial cells (Brayden
and Griffin 2008 ), nor do they appear to act in a compensatory fashion to prevent
CNS penetration of ivermectin inAbcb1a(/) mice (Schinkel et al. 1994 ). Studies
inAbcg2(/) mice also indicate no differences in brain concentrations of either
ivermectin or selamectin compared to wild-type mice (Geyer et al. 2009 ), further
strengthening the evidence that ABCB1 is the major transporter for avermectins on
the BBB. A model illustrating the influence ofP-gp on the PK of ivermectin is
shown in Fig. 4. Delivery systems that inhibitP-gp might restore ivermectin
sensitivity in resistant target organisms (Lespine et al. 2008 ), although a downside
could be increased CNS penetration in susceptible animals due to altered PK.
Membrane location and function of MRPs and ABCG2 on BBB endothelial cells
of different species have only been explored to a limited extent; most are thought to
serve as efflux pumps with overlapping and discrete sets of substrates and to be
located on the apical membrane. However, research in this field has been hampered
by practical difficulties in culturing isolated brain capillary endothelial cells
in vitro, including rapid de-differentiation with increasing passage number, differ-
ential transporter expression to that which occurs in vivo, and unusually low
102 D.J. Brayden et al.