ABC efflux transporters

Members of the ABC family, which are involved in the cellular export of drugs, comprise multidrug resistance (MDR) 1/P-glycoprotein, the multidrug resistance associated proteins (MRP), and breast cancer resistance protein (BCRP). 

OCTN 1 and OCTN2 (SLC22A4, SLC22A5) are expressed in human kidney, with OCTN2 also showing high expression in the small intestine [25]. In kidney both transporters are localized in the apical membrane of proximal tubules, whereas in intestine OCTN2 is localized in the brush border membrane of enterocytes. There it 

The members of the third subgroup OAT, such as OAT 1-3 (SLC22A6-8), are highly expressed in kidney, and localized in the basolateral membrane of proximal tubules. Only OAT2 shows a significant expression in liver. There it is localized in the basolateral membrane of hepatocytes [43], 

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CYP3A. DP7 is now considered a lead compound for the development of novel DHPs which do not affect CYP enzyme system but still retain the activity towards ABC-efflux transporters [110, 111]. Cardiac effects of DP7 using... 

P-glycoprotein is considered as the most important ABC efflux transporter (ABCBl, MDRl) at the blood-brain barrier [54]. It is a member of the ABC family and consumes ATP during its active efflux transport mechanisms. The major role of P-gp in the phenomenon of multidrug resistance is attributed to its broad substrate specificity. 

The incidence of phenytoin toxicity may be increased in the eideriy, or in those patients with hepatic or renal impairment, because of alterations in its pharmacokinetics. Plasma level determinations may be indicated in these cases. Although a role for P-glycoprotein transporter alleles in the development of phenytoin toxicity remains controversial, phenytoin is a robust substrate for the non-ABC efflux transporter RLIP76. Because RLIP76 has been found to be overexpressed in excised human epileptic foci, its action may account for treatment failures conversely, inhibition of transport may cause toxicity (34). There is a 2 to 3% increase in the risk of fetal epilepsy syndrome if the mother is taking phenytoin. Phenytoin is contraindicated in cardiac patients with bradyarrhythmias. Induction of CYP2C19 by ginkgo biloba may increase phenytoin clearance and precipitate serious seizures (35). 

ATP-binding cassette (ABC) transporters are efflux pumps that derive the energy needed for drug extrusion from the hydrolysis of ATP. Bacterial ABC antibiotic efflux transporter encoded on plasmids is a significant... 

For other efflux transporters such as BCRP (ABCG2), human pharmacokinetic and pharmacodynamic data are currently rare. However, an investigation of the influence of polymorphisms in ABC-transporter genes on the accumulation of nelfinavir in peripheral blood mononuclear cells (PBMCs) revealed no associations between the polymorphisms in the transporters analyzed and the accumulation of nelfinavir in the PBMCs [151], A second study in patients clearly demonstrated an increase in the AUC of the orally and intravenously administered BCRP substrate topotecan when it is given with GF120918, an inhibitor of P-glycoprotein and BCRP [152],... 

Schinkel, A.H. and Jonker, J.W. (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family an overview. Advanced Drug Delivery Reviews, 55, 3-29. 

Poor intestinal absorption of a potential drug molecule can be related to poor physicochemical properties and/or poor membrane permeation. Poor membrane permeation could be due to low paracellular or transcellular permeability or the net result of efflux from transporter proteins including MDRl (P-gp) or MRP proteins situated in the intestinal membrane. Cell lines with only one single efflux transporter are currently engineered for in vitro permeability assays to get suitable data for reliable QSAR models. In addition, efforts to gain deeper insight into P-gp and ABC on a structural basis are going on [131, 132]. 

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