What is an ABC Transporter?

How do ABC transporters work?

ABC transporters have two transmembrane domains (TMDs) forming the substrate translocation pathway and two nucleotide-binding domains (NBDs) that bind and hydrolyse ATP. Transport cycle: (1) substrate binds to inward-facing TMD from cytoplasm; (2) ATP binds to both NBDs → dimerisation → TMDs shift to outward-facing conformation; (3) substrate released extracellularly; (4) ATP hydrolysis → transporter resets.

Clinical significance of ABC transporter DDIs

Most important clinical examples: P-gp inhibition by ritonavir increases digoxin AUC by 86%; dual P-gp/BCRP inhibition by eltrombopag doubles rosuvastatin exposure; BSEP inhibition by troglitazone caused fulminant hepatic failure and market withdrawal; P-gp induction by rifampicin reduces digoxin bioavailability 30–40%.

Key Facts

• ABC = ATP-Binding Cassette — named after conserved nucleotide-binding domains that hydrolyse ATP to power transport
• Human genome encodes 48 ABC transporter genes divided into 7 subfamilies (ABCA–ABCG)
• Drug-relevant efflux transporters: P-gp (ABCB1), BCRP (ABCG2), BSEP (ABCB11), MRP1-8 (ABCC1-6, ABCC10-11)
• Location determines pharmacokinetic role: intestinal epithelium (limits oral absorption), BBB (limits CNS penetration), hepatocyte canalicular membrane (biliary excretion), renal tubule (urinary excretion)
• ABC transporters work as efflux pumps: substrate binds on intracellular face → ATP hydrolysis → conformational change → substrate released extracellularly
• FDA, EMA and ICH M12 require in vitro assessment of P-gp, BCRP, BSEP, and MRP family interactions for all NMEs

Further Reading

• What is P-glycoprotein (P-gp)?
• What is BCRP?
• What is BSEP?
• What is a Vesicular Transport Assay?
• Inside-Out Vesicles Explained

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