across species together with its tissue distribution suggests an important constitu-
tive protective function in the translocation of exogenous drugs and toxins.
With regard to drug delivery, the physiological distribution of ABC transporters
together with the structurally diverse nature of the xenobiotics with which they
interact significantly influences the pharmacokinetics, safety and efficacy of numer-
ous clinically-relevant veterinary compounds.P-gp interacts with hydrophobic,
hydrophilic, neutral, and charged molecules (Martinez et al2008a). Its substrates
include small molecules such as organic cations, carbohydrates, amino acids and
antibiotics (Zhou 2008 ), although no structure–activity relationship has been
clearly established. Transfected and non-transfected epithelial cell models are
used to screen for ABC transporter substrates, inhibitors and potential drug–drug
interactions in human drug development. Filter-grown polarised human Caco-
2 intestinal epithelial cell monolayers expressingP-gp are considered to be the
“gold standard” model for determining passive intestinal drug permeability
(Hubatsch et al. 2007 ) and can be used to screen verapamil-sensitive polarised
efflux ofP-gp substrates (Griffin et al. 2005 ). However, inter-species and inter-
regional differences in tissue transporter expression may occur and knowledge in
this area is sparse. Extrapolation from Caco-2 andABCB1-transfected monolayers,
such as the MDCK (Madin-Darby Canine Kidney) cell line, to in vivo circum-
stances in any species is therefore questionable. Furthermore, features of the widely
used Caco-2 model include over-expression ofP-gp, or variability inP-gp expres-
sion together with variable activity of the principal xenobiotic-metabolising
enzyme cytochrome P450 3A4 (CYP3A4) (Sun et al. 2008 ). As they act upon
common substrates, relative contributions ofP-gp and CYP3A4 to overall intestinal
permeation of xenobiotics may be difficult to determine accurately and may result
in inter-study discrepancies in reported drug PK parameters. Encouragingly how-
ever, there is evidence thatP-gp-expressing Caco-2 monolayers have similarP-gp
efflux activity to human (Makhey et al. 1998 ) and rat (Collett et al. 1999 ) intestinal
segments. Key parameters relating toP-gp such as substrate affinity, saturability
and capacity can be determined and are important in establishing the full influence
of efflux transporter mechanisms on oral bioavailability in vivo (Tang et al. 2002 ).
Although the regional distribution ofP-gp in veterinary species remains poorly
documented, inter-species differences in the presence ofP-gp in tissues is a feature
(Conrad et al. 2001 ). There are also differences in substrate-specificity between
species (Baltes et al. 2007 ). For example, while human MRP1 (ABCC1,
humMRP1) confers resistance to the anthracyclines such as doxorubicin, an
amino acid substitution at position 1089 (glutamate to glutamine) prevents interac-
tion with the rodent and canine homologues despite 88% and 92% sequence
homology with humMRP1, respectively (Stride et al. 1997 ; Ma et al. 2002 ). Further
research into species- and region-specific distribution of endogenous transporters
may lead to enhancement of both the efficacy and safety of species-specific drug
administration and also improve the design and outcome of preclinical PK and
toxicological studies in human medicine via more accurate data extrapolation
between species (Ma et al. 2002 ; Schrickx and Fink-Gremmels 2008 ).
Drug Delivery Systems in Domestic Animal Species 99