What is P-glycoprotein (P-gp / MDR1)?

Why does P-gp matter for drug development?

P-gp at the intestinal epithelium acts as a gatekeeper — pumping orally administered drugs back into the gut lumen, reducing bioavailability. A drug that is a P-gp substrate will have lower and more variable oral bioavailability, especially when co-administered with P-gp inhibitors. At the blood-brain barrier, P-gp limits CNS penetration — relevant for CNS-targeted drugs (where P-gp substrates fail to reach therapeutic concentrations) and for safety (where non-CNS drugs unexpectedly penetrate the BBB when P-gp is inhibited).

P-gp and multidrug resistance

P-gp was originally identified as the mechanism of multidrug resistance in cancer cells — tumour cells overexpressing P-gp pump out chemotherapy agents (vincristine, doxorubicin, paclitaxel), rendering them resistant to treatment. This is still a major challenge in oncology and drives development of P-gp inhibitors as chemosensitisers.

P-gp inhibition testing

For inhibitor IC50 determination — particularly for high-permeability compounds where cell-based efflux ratios are compressed — the vesicular transport assay with inside-out P-gp membrane vesicles provides permeability-independent IC50 values suitable for regulatory DDI cutoff calculations.

Key Facts

• Encoded by the ABCB1 gene (also called MDR1 — multidrug resistance protein 1)
• Expressed in: intestinal epithelium (limits oral absorption), blood-brain barrier (limits CNS penetration), hepatocyte canalicular membrane (biliary excretion), renal proximal tubule (urinary excretion), placenta
• Substrates include: digoxin, vincristine, paclitaxel, doxorubicin, HIV protease inhibitors, immunosuppressants (cyclosporin, tacrolimus), many statins
• P-gp inhibitors (verapamil, ketoconazole, ritonavir) increase bioavailability and CNS penetration of P-gp substrates — clinically significant DDI risk
• FDA and EMA require both substrate and inhibitor assessment for all NMEs in IND-enabling DMPK package
• In vitro assessment: cell-based bidirectional transport (Caco-2, MDCKII-MDR1) for substrate identification; vesicular transport assay for inhibitor IC50
• Cutoff: intestinal [I]/IC50 ≥ 0.1 or systemic Cmax,u/IC50 ≥ 0.02 triggers clinical DDI study requirement

Further Reading

• What is a Vesicular Transport Assay?
• FDA & EMA Mandatory Transporters for IND
• Vesicular vs Cell-Based vs ATPase Assay
• What is BSEP?

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