PharmacologyTier 1Medical Sciences concept

P-glycoprotein-mediated drug interactions

Core concept

P-glycoprotein (MDR1, ABCB1) - an ATP-dependent efflux pump that moves substrates out of cells, back into the lumen or blood
Sited wherever the body limits drug entry
- Enterocyte apical membrane -> pumps drug back into gut lumen -> dec oral bioavailability
- Blood-brain barrier endothelium -> dec CNS penetration
- Renal proximal tubule apical membrane -> inc active secretion
- Biliary canaliculus -> inc biliary excretion
- Placenta -> protects the fetus
Inhibition -> inc absorption, inc CNS entry, dec renal/biliary clearance -> inc plasma level and inc effect
Induction -> the reverse, dec level and therapeutic failure
P-gp and CYP3A4 share many substrates, inducers and inhibitors and act in series in the gut wall - the interaction is often both

Substrates	Inhibitors (inc level)	Inducers (dec level)
Digoxin	Verapamil, amiodarone, quinidine, clarithromycin, erythromycin, itraconazole, ketoconazole, ciclosporin, ritonavir, dronedarone	Rifampicin, carbamazepine, phenytoin, St John's wort
DOACs - dabigatran, rivaroxaban, apixaban, edoxaban	as above	as above
Ciclosporin, tacrolimus, sirolimus
Loperamide, colchicine, statins, fexofenadine
Vincristine, paclitaxel, doxorubicin

Dabigatran is a pure P-gp substrate with no CYP metabolism - the cleanest teaching example
- Potent P-gp inhibitors (itraconazole, ketoconazole, ciclosporin, dronedarone) are contraindicated or require dose reduction
- Verapamil -> dose reduction and separate administration
- Rifampicin -> contraindicated (loss of anticoagulation)
Digoxin + amiodarone or verapamil -> halve the digoxin dose and recheck the level
Loperamide is a P-gp substrate excluded from the CNS - P-gp inhibition (or massive overdose) gives central opioid effects and cardiac Na/K channel blockade
Tumour P-gp overexpression is a mechanism of multidrug resistance to vincristine, anthracyclines and taxanes
ABCB1 polymorphisms contribute to variable tacrolimus and digoxin exposure

Any new antibiotic, antifungal or antiarrhythmic in a patient on digoxin, a DOAC or a calcineurin inhibitor needs an interaction check
- Clarithromycin + digoxin, or clarithromycin + a DOAC, is a recurrent cause of admission
Rivaroxaban and apixaban are dual P-gp and CYP3A4 substrates - combined strong inhibitors (azoles, HIV protease inhibitors) are contraindicated
Loss of anticoagulant effect on rifampicin, carbamazepine, phenytoin or St John's wort is a silent failure - no monitoring test flags it
P-gp at the BBB explains why some drugs are non-sedating (fexofenadine, loperamide) despite high receptor affinity
Grapefruit juice inhibits intestinal CYP3A4 more than P-gp, but the effect is compounded

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