Elucidation of OATP1B1 and 1B3 transporter function using transgenic rodent models and commonly known single...

The clearance of many drugs from the blood into the liver, such as the statins, is dependent on the organic anion transporting polypeptides (OATPs). Patients with *5 and *15 polymorphisms of OATP1B1 remove less of the statin as it traverses the liver and thus more reaches the rest of the body, including the skeletal muscle where it can cause myalgia, myopathy, and rhabdomyolysis. OATP1B1 polymorphisms also affect the pharmacokinetics of anticancer drugs (methotrexate, taxanes, and doxorubicin) and numerous anti-hypertensive drugs. In contrast to OATP1B1, OATP1B3 does not appear to have polymorphisms of known physiological and pharmacological significance, except for Rotor patients, who have both defective OATP1B1 and OATP1B3 transport function. OATP1B1 and OATP1B3 also play important roles in the hepatic uptake of many endogenous molecules, such as bile acids, bilirubin, and coproporphyrins. However, the transport of individual bile acids is not well understood. Complete deficiency of OATP1B1 and 1B3 function in Rotor syndrome disrupts the hepatic reuptake of conjugated bilirubin with a corresponding clinical presentation as mild hyperbilirubinemia. Interestingly, cholecystokinin is only transported into the liver by OATP1B3. Hepatotoxicants such as the mushroom toxin phalloidin and the cyanobacterias toxin microcystin-LR are transported by the OATP1Bs as they are not hepatotoxic in Oatp1b2 "knock-out" mice. In conclusion, the OATP1Bs are important in the hepatic uptake of endogenous chemicals, drugs, and toxicants. Because there are polymorphisms of OATP1B1, knowledge of the genotype/phenotype is of importance in diagnosing and treatment of patients.