Published: September 2011
Publications
Medicines interactions: the role of P-glycoprotein
Prescriber Update 32(3): 21-22
September 2011
P-glycoprotein is the most well known of the transmembrane efflux transporters and first surfaced in the 1970s as the reason for multidrug resistance in cancer cells.
The general function of P-glycoprotein is now known to protect the body from harmful substances by:
- Removing drugs absorbed in the intestines back into the gut lumen.
- Maintaining the integrity of the blood brain barrier.
- Removing drugs from the kidneys and liver into the urine and bile respectively.
P-glycoprotein and medicine interactions
P-glycoprotein is partly responsible for the clearance of medicines via the renal and hepatic systems. This active transport system is saturable and can be inhibited or induced, leading to the potential for medicine-medicine interactions and medicine-food interactions.
The location in the body of P-glycoprotein mediated interactions varies and is important in determining whether an interaction is plausible or clinically relevant.
For example the interaction between loperamide and quinidine is due to the inhibition of P-glycoprotein at the blood brain barrier, resulting in adverse effects in the central nervous system.
The interaction between digoxin and verapamil takes place at P-glycoprotein located in the liver and kidneys, reducing the excretion of digoxin.
A medicine’s pharmacokinetic properties also influence P-glycoprotein interactions. Medicines that exhibit almost complete absorption from the gastrointestinal tract are less susceptible to interactions with P-glycoprotein inhibitors. Clearly gastrointestinal tract based P-glycoprotein interactions are irrelevant for intravenously administered medicines. The interaction between ketoconazole and dabigatran takes place in the intestine and results in increased absorption of dabigatran etixilate.
Clinically relevant P-glycoprotein mediated interactions
Up until recently, only digoxin and the beta blocker talinolol (not available in New Zealand) have been identified as medicines that are substrates for p-glycoprotein but are not metabolised by cytochrome P450.
Dabigatran is an anticoagulant medicine that is also now known to be influenced by P-glycoprotein. Dabigatran etexilate is a prodrug converted to its active form (dabigatran) following absorption from the gastrointestinal tract. Dabigatran etexilate is a substrate for P-glycoprotein; but the active dabigatran is not.
Since dabigatran etexilate is rapidly converted by plasma and liver esterases to its active form, P-glycoprotein interactions only take place in the gastrointestinal tract. This means the clinical significance of interactions with potent inhibitors is variable. For example, while clarithromycin increases the serum concentration of digoxin (renal site of interaction) it has no clinically relevant interaction with dabigatran (gastrointestinal site of interaction).
P-glycoprotein interactions do not routinely change plasma concentrations nearly as much as CYP450 interactions. Up until the approval of dabigatran these interactions were only clinically relevant for digoxin, due to its a low therapeutic index. Consequently extensive interaction studies have been performed for digoxin. To date only four substances have been reported to result in a greater than two fold change in digoxin C>max or AUC due to a P-glycoprotein interaction: valspodar, quinidine, amiodarone and ciclosporin.
Examples of medicines that may affect, or be transported by, P-glycoprotein are outlined in Table 2.
Healthcare professionals are advised to refer to the medicine data sheets available on the Medsafe website to check whether the potential interaction is clinically relevant.
Healthcare professionals are also reminded to report all suspected medicine-medicine and medicine-food interactions to CARM.
Table 1: Medicines affected by P-glycoprotein
| Inhibitors | Inducers | Substrates |
|---|---|---|
| Amiodarone | Rifampicin | Digoxin |
| Ketoconazole / Itraconazole | St John's Wort | Loperamide |
| Clarithromycin / Erythromycin | Carbamazepine | Colchicine |
| Ciclosporin | Phenytoin | Dabigatran etexilate |
| Verapamil | ||
| Diltiazem | ||
| Quinidine | ||
| Protease inhibitors | ||
| Sirolimus / Tacrolimus | ||
| Grapefruit juice |
References for further reading
- Fenner KS, Troutman MD, Kempshall S et al. 2008. ‘Drug-drug Interactions mediated through p-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug’ .Clin Pharmacol and Therapeut. 85 :173-181
- Lee CA, Cook JA, Reyner EL et al .2010. ‘P-glycoprotein related drug interactions: clinical importance and a consideration of disease states’ .Expert opinion Drug Metab Toxicol. 6: 603-619.
- Horn JR and Hansten PD .2004. ‘Drug interactions with digoxin: the role of p-glycoprotein’ .Pharmacy Times. 45-46.
- Sawyer J, Sharp J, Baxter K .2011. 'p-glycoprotein: why is it significant?' .Pharmaceutical J .286: 595-6.
- Baxter K (ed) .2010. Stockley’s Drug Interactions. Pharmaceutical Press, London
