Hepatobiliary elimination of cationic drugs: The role of P-glycoproteins and other ATP-dependent transporters

The liver plays a central role in the elimination of basic drugs. To fulfil this role, the liver is equipped with a number of uptake and excretion mechanisms for organic cations. A number of these transporters have been identified functionally and at the molecular level, At the level of uptake, at least three transporters have been identified, of which two have been cloned recently and seem to be involved in the uptake of cationic compounds; Oct1 and Oatp. Both proteins are discussed with regard to their contribution to cation uptake, along with other mechanisms that have been detected, At the level of the bile canaliculi, members of the ATP binding cassette (ABC) superfamily as well as a cation:proton antiporter seem to be involved in excretion of cationic drugs into bile, With regard to this aspect, current evidence for the involvement of various isoforms of P-glycoprotein and the multidrug resistance associated protein (MRP) in the biliary excretion process of cationic drugs is presented. The physiological and pharmacological role of P-glycoprotein in liver, including substrate specificity, regulation and induction of the transport protein are discussed, P-glycoprotein gene disruption studies in our laboratory demonstrate the essential function of this ATP-dependent transport system in hepatobiliary and intestinal transport of cationic drugs.