OATP other OATPs

R., Pizzagalli, F., Fattinger, K., Meier, P. J., Hagenbuch, B., Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver, Gastroenterology 2001, 120, 525-533. 

Tamai et al. [30] cloned OATP-B from human brain and transporter mRNA has been detected in a number of other tissues including liver, lung, kidney, placenta, brain, heart and small intestine [26, 30]. Within the liver, OATP-B protein is local-... 

There is evidence for the presence of other human OATPs including OATP-D [30], OATP-F (NM 017435] [39] and OATPRP4 (NM 030958). Further studies are required to determine the impact of these transporters on the drug distribution and elimination. 

All members of OATP/Oatp family contain 12 TM domains. Certain transporters show a more restricted tissue expression pattern (i.e., OATP1B1 [old name OATP-C]/liver), while others such as OATP2B1 (old name OATP-B) can be detected in almost every tissue that has been investigated [22], This indicates that some OATPs/Oatps have organ-specific functions, while others might be involved in housekeeping functions. 

Other mechanisms of interaction have also been reported, such as altered activity of other enzymes within the CYP450 family (14—17). Moreover, GFJ may also inhibit the intestinal P-glycoprotein (P-gp)-mediated efflux transport of drugs such as cyclosporine to increase its oral bioavailability (18-21). GFJ and other fruit juices have recently been shown to be potent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs) (22,23). 

In a more recent work, GFJ and orange juice have been reported to reduce the availability of fexofenadine and celiprolol (22,76,107). Both drugs are substrates for P-gp and OATP, but not CYP3A4 (108,109). If P-gp had played a major role in the observed interactions, the bioavailability would have been increased instead of decreased. This led to the conclusion that a mechanism other than P-gp was involved. In theory, the inhibition of OATP could lead to a decreased absorption of OATP substrates into intestinal enterocytes. This hypothesis was tested by several in vitro studies. 

Oatpla3 consists of two variants (Oat-kl and Oat-k2) in the kidney (69,70). Oat-k2 lacks 172 amino acids at the amino terminal (70). The localization of Oat-kl has been suggested to be brush border membrane of the renal tubules since polyclonal antibody detected Oat-kl only in the brush border membrane-enriched fraction from the kidney (71). In contrast to other Oatps, Oat-kl mediates facilitated transport since the uptake by Oat-kl was insensitive to an ATP depleter (sodium azide) (69). Oat-kl accepts only folate derivatives such as MTX and folate, while the substrates of Oat-k2 include TCA and prostaglandin E2 in addition to these folate derivatives (69,70). 

The first entirely synthetic derivative, fluvastatin (see Ref. [19]), and its subsequent derivative, atorvastatin, have a lipid solubility that is intermediate between pravastatin and the lactone prodrugs (see Tab. 4.2), and consequently their liver specificities are less expressed. In order to benefit from selective statin uptake mechanism into the liver cells and thereby decrease passive diffusion into other cell types, the recently introduced rosuvastatin molecule was purposefully made more hydrophilic by the introduction of a sulfonamide group. Indeed, the ratio of IC5 values measured in fibroblasts and hepatocyte cultures became considerable higher than that of atorvastatin (see Tab. 4.1). The pronounced differences of inhibitory potency, lipophilicity and the extent of active OATP-linked transport jointly... 

Inhibitors of OATP transport are typically ster-ically bulky compounds, including anions, cations, and neutral compounds (95). Various medications have been shown to interact with OATPs, including HMG CoA reductase inhibitors, cyclosporine, quinidine, rifampin, ketoconazole, verapamil, and certain protease inhibitors. Cyclosporine and rifampin have relatively high ratios of plasma concentration to Ki, suggesting the potential for clinically significant drug-drug interactions via modulation of OATP. On the other hand, plasma concentrations of pravastatin are... 

---