OAT transporters

TABLE 15.2 Drugs reported to interact with P-gp OATP, and OAT transport proteins ... 

In conclusion, OAIPs and sodium-independent OATs transport anionic compounds with a rather broad substrate specificity, whereas the sodium-dependent OATs have a narrow substrate specificity. Considering their substrates, it can be concluded that they have a similar physiological function as the MRPs in eliminating anionic compounds from the endothelial compartment. This may also be their major role at the BBB. Little is known about diseases related to malfunction of these transporters. 

The OAT Transporter Family Tissue Distribution, Localization and Substrate Specificity. Reprinted from American Journal of Physiology Renal Physiology, Volume 290, T. Sekine, H. Miyasaki and H. Endou, Molecular physiology of renal organic anion transporters, pp. 251-261, Copyright 2006, with permission from the American Physiological Society. 

Another family of transporters, the a-ketoglutarate organic anion exchangers (OAT transporters), have been demonstrated to transport prostanoids. This transport appears to be relatively non-specific and the prostanoid substrate selectivities have not been well explored beyond that of PGEj (Schuster, 2002). 

An in vitro and in vivo study showed a drug interaction between penicillin and acyclovir by means of inhibition of OATl and OATS transporters, subsequently decreasing the renal excretion of acyclovir. Patients should be monitored closely for acyclovir adverse effects when given in combination with penicillin [45 ]. 

Importantly, the currently available transporter models only cover a small fraction of all transporters involved in drug disposition. Other than incorporating current stand-alone transporter models into systemic models to directly predict drug pharmacokinetic properties, continued efforts are still needed to investigate other transporters such as MRP, BCRP, NTCP, and OAT, to get a more complete understanding of the drug pharmacokinetic profile. 

R. Pinton, Z. Varanini, G. Vizzotto, and A. Maggioni, Soil humic molecules affect transport properties of tonoplast vesicles i.solated from oat roots. Plant Soil 142 203 (1992). 

Effects of Allelochemlcals on ATPases. Several flavonoid compounds inhibit ATPase activity that is associated with mineral absorption. Phloretin and quercetin (100 pM) inhibited the plasma membrane ATPase Isolated from oat roots (33). The naphthoquinone juglone was inhibitory also. However, neither ferulic acid nor salicylic acid inhibited the ATPase. Additional research has shown that even at 10 mM salicylic acid inhibits ATPase activity only 10-15% (49). This lack of activity by salicylic acid was substantiated with the plasma membrane ATPase Isolated from Neurospora crassa (50) however, the flavonols fisetln, morin, myricetin, quercetin, and rutin were inhibitory to the Neurospora ATPase. Flavonoids inhibited the transport ATPases of several animal systems also (51-53). Thus, it appears that flavonoids but not phenolic acids might affect mineral transport by inhibiting ATPase enzymes. 

Aungst, B. J. Nguyen, N. H. Bulgarelli, J. P. Oates-Lenz, K. The influence of donor and reservoir additives on Caco-2 permeability and secretory transport of HIV protease inhibitors and other lipophilic compounds, Pharm. Res. 17, 1175-1180 (2000). 

In cell lines, the organic anion transporters (OAT and OATP) have been identified and cloned into cells of kidney origin such as LLC-PK1, MDCK, HK-2, and Caco-2 [129]. The most well-known uptake transporters, which transport the substrate over the membrane into the organism are the amino acid- [35, 42, 139] and oligopeptide-carriers (PepTl and PepT2) [139-142]. These two transporter families are abundantly expressed in the small intestine of most animals, and can therefore be involved in the absorption process of pharmaceutical drugs. The PepTl is expressed in the cell lines Caco-2 and HT-29 [140-142]. 

Organic anion transporters can be divided into three major families organic anion transporters (OATs), organic anion transporting polypeptides (OATPs), and multidrug resistance associated proteins (MRPs) [201]. 

Endou. The multispecific organic anion transporter (OAT) family. 

In addition to OATP/Oatp family proteins, some of the organic anion transporter (OAT) family proteins may be responsible for hepatic uptake. Although many OAT family proteins are expressed in the kidney [36], human and rat OAT2 is also expressed in the liver [37, 38]. Human OAT2 transports p-amino-... 

Within the OAT family, OAT4 is the only transporter expressed at appreciable levels in both the placenta and in the kidney [54]. The membrane localization of OAT4 within these tissues has not been examined. Steroid sulfates, and ochratoxinA are efficient transport substrates of OAT4, whereas PAH is weakly transported [54]. The functional importance of OAT4 in regulating placental permeability and renal drug elimination is currently unknown. 

Sekine T, Cha SH, Endou H. The multispecific organic anion transporter (OAT) family. Pfliigers Arch 2000 440(3) 337—350. 

It is significant that oat plants, which are known to contain the Fe3+ complexor, 2,4-dihydroxy-7-methoxy-l,4-benzoxazin-3-one (128), do not show any significant accumulation of plutonium, or the other actinides. It is possible that this complexing agent is located within plant cells which do not come into contact with the cation transporting mechanisms. Although there is evidence of the existence of microbial hy-droxamates in soil and that hydroxamates do become concentrated in plants (129), there has been no evidence presented yet that hydroxamates are the agents responsible for plutonium uptake into plants. On the other hand there is evidence that EDTA and DTPA can stimulate actinide concentration in plants (See Table 6). 

Groneberg DA, Eynott PR, Doring F, Dinh QT, Oates T, Barnes PJ, Chung KF, Daniel H, Fisher A (2002) Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung. Thorax 57 55-60. 

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