Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics.
OBJECTIVE
Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated transport contributes to hepatic uptake and/or biliary excretion. In particular, primary active transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as "Phase III" (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation.


METHODS
The transporters, which have been called P-glycoprotein (MDR), multidrug resistance related protein (MRP) and GS-X pump and which are believed to be involved in the primary active pumping of xenobiotics from the cells, are now known as the ATP-binding cassette (ABC) transporters. In this review, we first describe the HMG-CoA reductase inhibitor, pravastatin, as a typical case of a carrier-mediated active transport system that contributes to the liver-specific distribution in the body.


RESULTS
Regarding biliary excretion, we have summarized recent results suggesting the possible contribution of the ABC transporters to the biliary excretion of xenobiotics. We also focus on the multiplicities in both hepatic uptake and biliary excretion mechanisms. Analyzing these multiplicities in transport is necessary not only from a biochemical point of view, but also for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics.


CONCLUSIONS
Clarification of these transport mechanism may provide important information for studying the pharmacokinetics of new therapeutic drugs and furthermore, leads to the development of the drug delivery systems.
Yamazaki
M
M
Department of Pharmacokinetics & Biopharmaceutics, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Suzuki
H
H
Sugiyama
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism*; D001693:Biological Transport, Active; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000639:trends; D018432:Drug Resistance, Multiple / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000378:metabolism*; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017035:Pravastatin / Q000378:metabolism; D051381:Rats; D015262:Xenobiotics / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017035:Pravastatin; D015262:Xenobiotics