P-Glycoprotein

Abstract

According to the report of Agency for Healthcare Research and Quality in 2008, drug-related adverse outcomes exceed 2.7 million events per year. Therefore, it is requisite to understand the etiologies of those unpleasant outcomes. Polypharmacy especially in the elderly is considered one of the major sources of drug-related side effects. The drug-related membrane transporters play an indispensable role in the pharmacokinetics, safety, and efficacy of the drugs. P-glycoprotein, also known as P-gp, is considered one of the core drug transporters in vivo. Since its discovery in 1976, P-gp gained a tremendous attention of researchers and clinicians. The core objective of this review is to highlight the clinical correlation between the P-gp and a number of cardiovascular drugs and to address the drug-drug interaction in case of using those cardiovascular drugs with P-gp-related drugs whether substrates, inhibitors, or inducers. Bearing in mind that P-gp is found in liver and intestine, as well as cytochrome P450, a strong association between the 2 systems is expected. Yet, plenty of the drugs that can behave as substrates to P-gp can act as substrates to CYP450 too. Consequently, probable drug-drug interaction can occur between drugs that work on both systems. In other words, whenever these classes of medications prescribed together cautious monitoring of drug's level and eventually dose adjustment might be necessary to avoid drug-drug interactions, failure of therapy, or drug toxicity; especially with the use of drugs that possess narrow therapeutic index like digoxin.

Repurposing colchicine’s journey in view of drug-to-drug interactions. A review

“…Rosuvastatin, pitavastatin, fluvastatin and pravastatin show minimal to no interaction with the above-mentioned enzymes and can be safely prescribed with colchicine [ 31 ]. Although atorvastatin, simvastatin and lovastatin appear to affect the activity of these enzymes, chronic co-administration with colchicine was safe in LoDoCo-2 and COLCOT [ 31 , 32 ]. A modified dosing scheme has been suggested for those statins only, with a loading dose not exceeding 1.2 mg and a daily maintenance scheme not exceeding 0.6 mg qd [ 31 ].…”

“…If the use of an agent from this class is of importance, the dihydropyridine agent amlodipine could be safely used because it shows only weak inhibitory effect on CYP3A4 [ 17 ]. Although the beta-blockers propranolol, carvedilol and bisoprolol exhibit P-glycoprotein inhibitory effects [ 32 ], no safety issue was observed with the concomitant use of colchicine in COLCOT. Renin-angiotensin-aldosterone system inhibitors (RAASi) seem to be deprived of P-glycoprotein effects, apart from telmisartan [ 17 , 35 , 36 ].…”

“…Regarding the coadministration of colchicine with anti-arrhythmic drugs (AADs), amiodarone and dronaderone inhibit the P-glycoprotein efflux system [ 37 ]. In contrast, the class III β-blocking AAD sotalol can be safely administered with colchicine [ 17 , 32 ]. Finally, DOACs (direct oral anticoagulants) have no clinically important effect on CYP3A4 and P-glycoprotein activity, while warfarin is considered to be a P-glycoprotein inhibitor warranting colchicine dose reduction if high-dose colchicine is used [ 17 , 32 ].…”