Phase-3 = active transmembrane transport that determines drug absorption, distribution, biliary + renal excretion. Efflux pumps (ABC family): P-glycoprotein (P-gp / ABCB1 — broad substrate; gut barrier + BBB + biliary; digoxin / colchicine / fexofenadine); BCRP (ABCG2 — overlapping with P-gp; rosuvastatin); MRP family (ABCC1-7 — glucuronide / glutathione conjugates). Uptake pumps (SLC family): OATP1B1/B3 (hepatic uptake of statins; SLCO1B1 polymorphism affects simvastatin myopathy risk); OCT2 (renal cation uptake; metformin); MATE1/2 (renal cation efflux; cobicistat blocks → mild creatinine rise). Cobicistat + ritonavir + verapamil are clinically important P-gp + OATP inhibitors. Rifampin is a P-gp inducer (digoxin AUC reduction).
Organ Systems
digestive
renal
nervous
Pathway Steps
lumenal-drug → enterocyte-or-blocked — via P-gp efflux at gut barrier (limits absorption). Phase III refers to membrane transporters that move drugs across barriers — the disposition step after phase-I/II metabolism. At the intestine, efflux pumps like P-glycoprotein (MDR1) pump drug back into the lumen, limiting oral absorption and underlying many drug-drug interactions.
portal-blood-drug → hepatocyte — via OATP1B1 / OATP1B3 uptake (statins, irinotecan). Uptake transporters (OATPs) on the hepatocyte sinusoidal membrane carry drugs from portal blood into the liver — the entry step for hepatic clearance. OATP inhibition (by some drugs or grapefruit components) raises plasma levels of statins and other substrates, a key interaction mechanism.
hepatocyte-drug → bile — via P-gp / BCRP / MRP2 canalicular efflux. Canalicular efflux transporters (MRP2, BCRP, BSEP) then pump drugs and conjugates from the hepatocyte into bile for elimination. This biliary excretion completes clearance; its inhibition (e.g. BSEP blockade) causes drug-induced cholestasis, a recognized hepatotoxicity mechanism.