4.2  The SLC superfamily
A large body of evidence demonstrates that the solute carrier (SLC) superfamily plays a crucial role in the efflux transport of organic compounds, organic anions particularly, across the BBB (Kusuhara and Sugiyama, 2005). Some members of this superfamily include organic anion-transporting polypeptide (OATPs), organic anion transporters (OATs) and organic cation transporters (OCTs). These ATP and sodium-independent polypeptides are expressed in a variety of tissues including the brain capillary endothelium and choroid plexus epithelial cells and regulate the movement of drugs through the brain barriers.

4.2.1  OATPs
All Oatp/OATPS are members of the SLC21 family and 36 Oatps/OATPS have so far been identified in humans, rats and mice (Hagenbuch and Meier, 2004). Several studies have shown that these transporters have a role in the efflux of organic compounds. The expression of OATP1A2 and OATP1C1 have been found in the BBB and the brain, respectively. In rats, Oatp1a4, Oatp1a5 and Oatp1c1 are expressed at the BBB and the blood–CSF barrier (Kusuhara and Sugiyama, 2005). OATP has been implicated in the removal of 2′3′-dideoxycytidine (ddC; zalcitabine) from the brain and CSF (Gibbs and Thomas, 2002). Oatp2 is found at the cerebral capillary endothelium and the choroid plexus epithelium, suggesting a role for these carriers in the transport of drugs between the blood and CNS compartments (Gao et al., 1999). An Oatp-2 like transporter has been implicated in the uptake of the NRTIs, 2′,3′-dideoxyinosine (ddI, didanosine) and (−)-2′-deoxy-3′-thiacytidine (3TC, lamivudine) into the choroid plexus (Gibbs and Thomas, 2002; Gibbs et al., 2003a,b). HIV may enter the CNS via the choroid plexus and therefore transporters present at this site could play an important role in CNS efficacy of certain drugs.

4.2.2  OATs
This family of transporters comprise OAT1, OAT2, OAT3, OAT4 and RST. UST1, UST3 and OAT5 are also considered as transporters of organic anions, however this has not yet been proven (Anzai et al., 2006). The recently identified urate transporter, URAT1 is very similar to RST in terms of amino acid sequence and tissue distribution. Additionally, URAT1 appears to be the human ortholog of murine RST and rat OAT1 (Eraly et al., 2004). Many drugs exist as organic anions at physiological pH levels and therefore OATs present must have a pivotal role in handling these compounds. Studies using Xenopus laevis oocytes showed that antiretroviral nucleoside drugs are substrates for OAT proteins despite the fact that they are not conventional organic anions (Strazielle et al., 2003).
Oat3 is present in the rat brain capillaries (Ohtsuki et al., 2002). There is no direct evidence for the expression of Oat1 at the BBB, however, it is suggested that the observed efflux of certain substances known to be Oat1 substrates from brain to blood indicates that the presence of Oat1 is likely (Sun et al., 2003). ddC and AZT are thought to be removed from the brain by a member of the OAT family (Takasawa et al., 1997; Gibbs and Thomas, 2002; Strazielle et al., 2003). OAT1 and 3 are expressed in the human, murine and rat choroid plexus (Sweet et al., 2002; Alebouyeh et al., 2003) and seem to be largely important in determining the availability of organic anions in the CSF (Eraly et al., 2004). These isoforms are likely candidates for the uptake of CSF-borne AZT and ddC (Gibbs and Thomas, 2002; Strazielle et al., 2003). However, the efflux of AZT was inhibited by specific inhibitors of both of these transporters, which makes it difficult to attribute a particular isoform to this effect.
Anthonypillai et al. (2006) investigated the distribution of a prodrug of the NRTI tenofovir, known as PMPA to the brain, CSF and choroid plexus. Interestingly, the entry of this pro-drug into the brain was negligible, but it could reach the CSF. The presence of a transporter at the level of the choroid plexus was indicated. Since hOAT1 and hOAT3 are high- and low-affinity transporters of PMPA, respectively (Cihlar et al., 2001; Izzedine et al., 2005), the involvement of these carriers was speculated however no detectable interaction was observed (Anthonypillai et al., 2006).

4.2.3  OCTs
The literature concerning OCT expression in the brain is at times contradictory, and this maybe the result of variation between species and also differing area and levels of expression of the transporters within the brain (Sweet et al., 2001). A study by Slitt et al. (2002) found that mRNA for all five organic cation transporters could be detected in the rat brain. Although this work did not evaluate whether the transporters were present at the brain barriers, additional studies have provided some evidence for the presence for individual organic cation transporters at the BBB and choroid plexus. It has been established that OCTN2 is found on the luminal face (and possibly the abluminal face too) of the cerebral capillary endothelial cells of humans, rats, pigs and cows (Kido et al., 2001). OCT2, OCT3, OCTN1 and OCTN2 (but not OCT1) are also expressed in the rat choroid plexus (Sweet et al., 2001). Human OCTs play a crucial role in the initial step involved in hepatic or renal excretion of many cationic compounds. Furthermore, previous studies have demonstrated the involvement of rat OCTs and an undefined organic cation-proton exchanger in the cellular uptake of AZT and 3TC, raising the possibility that human OCTs could also be involved in the uptake of anti-HIV drugs (Minuesa et al., 2008). Moreover, Minuesa et al. (2008) revealed that hOCTs were heterogeneously expressed in primary lymphocytes, monocytes, macrophages and dendritic cells. These transporters were also upregulated upon lymphocyte activation.
A recent study suggested that the PIs, nelfinavir, ritonavir, saquinavir and indinavir are possibly inhibitors of OCT1 and OCT2 (Jung et al., 2008). This supported evidence provided by Zhang et al. (2000) that some HIV PIs may be potent inhibitors of cationic drug uptake, but poor substrates for human OCT1 (Zhang et al., 2000). Furthermore, the NRTIs, lamivudine and zalcitabine are substrates of OCT1 and OCT2 (Jung et al., 2008). Moreover, when assessing the expression of OCTs in lymph nodes of HIV-infected patients in comparison to healthy controls, Jung and colleagues found that OCT1 and OCT2 were upregulated in the lymph nodes of HIV-infected patients, indicating that the accumulation of OCT substrates would be much higher in the lymph nodes of these patients. This could be due to the activation of the immune system and effects of cytokines induced by HIV infection (Jung et al., 2008). This study implies that a sound knowledge of OCTs is crucial in understanding both drug interactions that may occur with HAART and also the role they play in regulating drug transport.