substrate for transporters that influence absorption, distribution and elimination. For
example, although ivermectin systemic bioavailability is sufficiently high to pro-
vide therapeutic concentrations from a range of formulations, its distribution across
the blood–brain barrier (BBB) of mammalian species and its elimination via the
bile duct and kidneys are regulated by the efflux transport protein,P-glycoprotein
(P-gp). These transporters therefore exert significant effects on the pharmacological
outcomes of drugs delivered exogenously and they may influence choice of deliv-
ery technology and route of administration. They may also be responsible for drug–
drug interactions. While a range of transporters may influence drug delivery, most
published literature to-date has focused on the ATP-binding cassette (ABC) super-
family of efflux transporters, probably the most significant family of membrane
transport proteins (Martinez et al.2008a). Most in vitro systems and in vivo models
have been developed for studying the transport of drugs and nutrients in human
rather than veterinary medicine. Consequently, more is known about transporter
expression and function in laboratory animal models and human tissues than in
veterinary species. As the dog is often used as a model for evaluating human
formulations, there are more data on its transporters than those present in cats and
livestock, but still less than in other laboratory animals (Li et al. 2008 ).
4.1 ABC Efflux Transporters in Veterinary Medicine
ABC efflux transporters are members of a family of ATP-dependent pumps. These
membrane spanning structures are expressed widely in both prokaryotic and
eukaryotic cells. Their principal function is transport of a range of substances
against their concentration gradient (Davidson and Maloney 2007 ). There is also
evidence that they may be involved in integral physiological functions, including
immunological processes and cell proliferation, differentiation and death
(Johnstone et al. 2000 ). Although their potential role in drug delivery remains to
be fully determined, it is evident that regulated expression of ABC transporters
confers multi-drug resistance (MDR) in tumour cells (Juliano and Ling 1976 ) and
they are also involved in antibacterial drug resistance (Quinn et al. 2006 ).
The first of the ABC transporters to be discovered and characterised wasP-gp,
thetrans-membrane pump product encoded by theMDR1(re-namedABCB1) gene.
A number of these transporters play a central role in phase 0 metabolism (efflux of
xenobiotics upon cell permeation) and phase III metabolism (efflux of xenobiotic
metabolites), both of which are important steps in defence against xenobiotics
(Dietrich et al. 2003 ).P-gp is predominantly located in apical membranes of
enterocytes (gut epithelial cells), membranes of brain capillary endothelial cells
at the BBB, biliary canalicular epithelial cell membranes, renal proximal tubular
epithelial cells, and placental trophoblasts (Martinez et al.2008a). Although it is not
essential for normal physiology and fertility, at least inAbcb1a (/) mice,
(Schinkel et al. 1994 ), the highly conserved nature of theP-gp amino acid sequence
98 D.J. Brayden et al.