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Transporters (Figure 1.7a) play an important role in enhancing or limiting the disposition of drugs (Ho and Kim, 2005) in plasma, target issue, as well as in blood–brain barrier (Shen and Zhang, 2010) as shown in Table 1.2. About 400 genes code for transporters in human and animals and these are classified into two large super‐families – the solute carrier or SLC superfamily containing 364 proteins in 48 subfamilies (Fredriksson et al., 2008) and the ATP‐binding cassette or ABC transporters of 49 proteins in 7 subfamilies. The SLC transporters mediate cellular influx of substrates either by facilitated diffusion or by secondary active transport, driven by co‐transport (symport or antiport) of endogenous organic ions (Zhang et al., 2002; Hediger et al., 2004; Hagenbuch and Gui, 2008; Duan and You, 2010). ABC transporters mediate the primary active transport of unidirectional efflux of drugs often against a steep diffusion gradient, deriving energy from ATP hydrolysis (Van De Water et al., 2005; Szakács et al., 2008; Schinkel and Jonker, 2012). The transporters that play an important role in human disposition are the active SLC transporters OATP1B1, 1B3 and 2B1, SLC transporters that mediate facilitated diffusion OCTs 1 and 2, SLC antiport transporters MATE1 and MATE2K, and the ABC efflux transporters P‐gp (MDR1), MRP2 (important in the transport of glucuronide and glutathione conjugates), BCRP and BSEP. ATP‐independent secondary efflux transporters are probably present an additional mechanism for toxin extrusion even if cells are energy‐deprived. The different types of transporters are shown in (Figure 1.7b).

Figure 1.7. (a) Uptake and efflux drug transporters in intestine, liver, kidney, and brain. OAT, organic anion transporter; OATP, organic anion‐transporting polypeptide; NTCP, sodium taurocholate cotransporting peptide; OCT, organic cation transporter; OCTN, novel‐type OCT; PEPT, oligopeptide transporter; ASBT, apical sodium‐dependent bile acid transporter; MDR, multidrug‐resistant (or resistance); MRP, multidrug resistance‐associated protein; BCRP, breast cancer resistance protein; MATE, multidrug and toxin extrusion; MCT, monocarboxylate transporter; OST, organic solute transport; URAT, urate transporter. (b) Primary active ATP‐Binding Cassette (ABC) efflux transporters derive energy from the hydrolysis of ATP to ADP and are shown in dark shade. The secondary active transporter families or solute carrier (SLC) uptake transporters, utilize either ion gradients across membranes or cotransport with intracellular and/extracellular ions. These are either symports (unshaded) or antiports (lightly shaded). Multi‐drug efflux pump, MATE is a cation‐coupled family of transporters. OST α/β is a heterodimer that together transports bile acids, conjugated steroids, and structurally related molecules. Clinically relevant transporters are shown in bold (Source: Ho and Kim 2005).

TABLE 1.2. Role of transporters in ADME.

ADME	Transporter	Example	Role
Absorption	Carriers	PEPT	Enhances absorption by transporting hydrophilic compounds with specific groups like peptide linkages
Absorption	Efflux	P‐gp BCRP MRP2	Limits absorption of large lipophilic molecules. P‐gp has broad specificity
Absorption	Uptake	OATP	Uptake of organic ions
Distribution	Uptake, efflux	Various	Increases or decreases tissue distribution
Metabolism	Uptake	OATP1B1 OATP1B3 OATP2B1	Increases or decreases exposure to drug‐metabolizing enzymes thereby increasing or decreasing metabolism
Biliary elimination	Efflux	P‐gp BCRP	Increases biliary elimination of lipophilic, amphiphilic compounds
Renal elimination	Uptake	OAT 1,2,3 OCT2 OATP4C1	Increases uptake and elimination of hydrophilic compounds
Renal elimination	Efflux	P‐gp, MATE1, MATE2‐K MRP2, 4	Removal (active secretion) of toxins

The role of the efflux transporter P‐gp in restricting absorption, transporting amphiphilic compounds into bile and keeping out lipophilic compounds from the brain has long been recognized. It is difficult to predict the disposition of compounds that are transported, as the substrate specificity to most transporters are dependent on the chemical structure of the drug. However, there are some general principles for identifying transporter substrates (Wright and Dantzler, 2004; El‐Sheikh et al., 2008; Nies et al., 2008; Ahn and Nigam, 2009; Kusuhara and Sugiyama, 2009). For example, P‐gp substrates are mostly large and lipophilic. Substrates of the uptake transporter OATP1B1 are mostly carboxylic acids and so on. Efflux transporters like MRP2 and BCRP have similar substrate specificity to uptake transporters, reducing the possibility for toxin accumulation.

Absorption, distribution, renal elimination, and biliary elimination are all dependent on physicochemical properties of the drug, particularly lipophilicity and acid/base/neutral characteristics and physiology of the species like blood flow, organ volumes, transit rates etc. The chemical structure of a drug dictates its rate and extent of biotransformation as well as affinity to transporters.

Although in vitro assays may identify potential substrates of transporters, their relevance in vivo depends very much on the expression levels of transporters in the tissue and on the concentration of the drug relative to its K_M . If the affinity of the drug to the protein is high (low K_M ) and/or the drug concentrations are high, the transporters are easily saturated. For example, P‐gp efflux in the enterocytes is easily saturated by many of its substrates. The rate of P‐gp efflux in the gut also depends on the membrane permeability of the drug and the rate of gut metabolism. For high permeability drugs with high gut extraction, the rate of efflux is low. The impact of uptake or efflux transporters in increasing or decreasing intracellular concentrations of their substrates is much more for low permeability drugs compared to high permeability drugs. P‐gp and CYP3A4 share a common substrate specificity. In the gut, where drug concentrations can be high, this enzyme–transporter interplay (Benet, 2009) increases the probability of contact between the drug and enzyme, by making it possible for CYP3A4 to remain unsaturated due to the dilution effects of P‐gp efflux. The mean residence time of drug and enzyme also increases, as the drug is presented to the enzymes repeatedly while it transits down the small intestine. P‐gp efflux however, also offers a competing mechanism to metabolism both in the liver and in the gut. The roles of renal anionic and cationic transporters in drug disposition have been reviewed (Dresser et al., 2001; Masereeuw and Russel, 2010).