The role of hepatic transporters in drug elimination
COMMENT: This article helps develop a picture of hepatic cells transporters, both the ABC and the SLC superfamilies and of the drugs they transport. ABC effluxers line the bile canniculi and export drugs into the bile while the SLCs are poised on the basolateral or blood border and influx drugs, both anionic and cationic. Phase 1 and 2 metabolic structures lie in between. Unlike the CYPs, but like the UGTs, both families of transporters handle both endogenous and exogenous compounds. As example, SLCO1B1 (OATP1B1) imports into the hepatic cell both bile salts as well as a variety of drugs including the statins, bosentan, olmesartan and valsartan. This sets up the possibility of many drug interactions when drugs that are SLCO1B1(OATP1B1) inhibitors are added to drugs that are substrates of the same transporter. Gemfibrozil inhibits SLCO1B1 and levels of pravastatin double since the drug can no longer be influxed into the hepatic cell and sent along to the bile by ABCC2. Instead pravastatin stays in the systemic circulation. These transporter-based DDI are just coming into the scientific literature with the development of more specific probes and knock out mice.
ABSTRACT: The role of hepatic transporters in drug elimination. Funk C.
BACKGROUND: Hepatic drug transporters of the solute carrier (OATPs, OAT2, OCT1, NTCP) and ABC transporter superfamilies (MDR1, MRPs, BCRP, BSEP) can significantly modulate drug ADME routes.
OBJECTIVE: The currently available literature was reviewed with focus on hepatic drug transporters, related drug-drug interactions and available tools for transporter assessment and extrapolation to in vivo.
CONCLUSIONS: Hepatic drug transporters have gained additional importance in drug clearance by optimization for basic DMPK properties early on in drug research. However, the lack of selective substrates and inhibitors, proper assessment of the kinetic properties due to interfering passive permeability and multiple binding sites, as well as endogenous transporters present in many cellular assays, are some of the hurdles in studying active drug transport processes. Therefore, data from these in vitro assays have to be carefully evaluated to allow sound extrapolation to the in vivo situation.