Table 1.

Examples of studies in which membrane transporters have been shown to alter hepatocellular drug concentrations

Transporter (gene)	Localization and directionality	Substrate	Effect on intracellular concentrationsa	Effect on plasma exposurea	Observationb	Model system
MRP2 (ABCC2)	Canalicular Efflux	99mTc-Mebrofenin	↑	NA	Prolonged and increased hepatobiliary exposure in patients with genetically impaired MRP2 function23	Humans in vivo
		7-Hydroxymethotrexate	↑	↑	Hepatic accumulation of 7-hydroxymethotrexate26	Mrp2−/− mice
		Valproate glucuronide	↑	NA	Inhibition by probenecid increased hepatic exposure27	Isolated perfused rat livers
MRP3 (ABCC3)	Basolateral efflux	7-Hydroxymethotrexate	↑	↑	Pronounced accumulation of 7-hydroxymethotrexate26	Mrp2−/−/Mrp3−/− mice
		Valproate glucuronide	↑	NA	Inhibition by probenecid increased hepatic exposure27	Isolated perfused rat livers
		Unconjugated bile acids	↓	↑	Induction by ANIT decreased hepatic concentrations29	Mice
BCRP (ABCG2)	Canalicular Efflux	Rosuvastatin	(↑)	NA	Reduced-function polymorphisms increased hepatic efficacy24,25,76	Humans in vivo
		Nitrofurantoin	↑	NA	RNA interference knockdown reduced in vitro biliary clearance77	Sandwich-cultured rat hepatocytes
OCT1 (SLC22A1)	Basolateral uptake	Metformin	(↓)	↔	Reduced-function polymorphisms limited the pharmacological effect20	Humans in vivo
		Metformin	↓	↔	Reduced hepatic concentrations18	Oct1−/− mice
OATP1B1 (SLCO1B1)	Basolateral uptake	Methotrexate	(↓)	↑	Reduced-function polymorphisms decreased gastrointestinal toxicity and increased plasma concentrations78	Humans in vivo
		Methotrexate	↓	↑	Decreased hepatic concentration and increased plasma exposure70	Oatp1a−/−/1b−/− mice
		Gadoxetate disodium (MRI contrast agent)	↓	NA	Inhibition by lapatinib decreased hepatic parenchymal enhancement17	Humans in vivo
		Pravastatin	↓	↑	Decreased hepatic concentrations79	Oatp1a−/−/1b−/− mice
MATE1 (SLC47A1)	Canalicular efflux	Metformin	↑	↑	Increased hepatic concentrations80	Mate1−/− mice
			NA	↔	Reduced-function polymorphic variants enhanced glucose-lowering effects of metformin81	Humans in vivo

ANIT, alpha-naphthyl isothiocyanate; AUC, area under the concentration–time curve; BCRP, breast cancer–resistance protein; MATE, multidrug and toxin extrusion protein; MRI, magnetic resonance imaging; MRP, multidrug-resistance protein; NA, data are not available; OATP, organic anion–transporting polypeptide; OCT, organic cation transporter.

^aUp and down arrows indicate increased and decreased intracellular concentrations (or plasma AUC), respectively. Left–right arrows indicate no significant change. Parentheses denote examples for which the effect on intracellular concentrations is not directly measured but instead implied from pharmacological or toxicological observations.

^bRefs. 76–98 are listed in Supplementary Data online.