Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein

Abstract

Proton pump inhibitors are a class of drugs which are widely prescribed for acid-related diseases. They are primarily metabolized by CYP2C19 and CYP3A4. It is unknown so far whether proton pump inhibitors are also substrates of the ATP-dependent efflux transporter P-glycoprotein. Moreover, it is not established whether proton pump inhibitors are also inhibitors of P-glycoprotein function. The aim of our study was therefore to characterize omeprazole, lansoprazole and pantoprazole as P-glycoprotein substrates and inhibitors. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells. Inhibition of P-glycoprotein-mediated transport was determined using the cyclosporine analogue PSC-833 (valspodar) as P-glycoprotein inhibitor. Inhibition of efflux transport by omeprazole, lansoprazole and pantoprazole was assessed using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, basal-to-apical transport of omeprazole, lansoprazole and pantoprazole was greater than apical-to-basal transport in Caco-2 and L-MDRI cells. Addition of PSC-833 (1 microM) showed a clear effect only for lansoprazole, suggesting that other transporters contribute to omeprazole and pantoprazole cellular translocation. Furthermore, all of the tested compounds inhibited digoxin transport with IC50 values of 17.7, 17.9 and 62.8 microM for omeprazole, pantoprazole and lansoprazole, respectively. In summary, our data provide evidence that proton pump inhibitors are substrates and inhibitors of P-glycoprotein. These findings might explain some of the drug interactions with proton pump inhibitors observed in vivo.

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

“…Recently it has been reported that benzimidazole gastric H ϩ , K ϩ -ATPase proton pump inhibitors (PPIs-omeprazole, pantoprazole, lansoprazole, and rabeprazole), which are used by up to 50% of patients with cancer, are effective inhibitors of P-gp in vitro [45], although their potency towards BCRP inhibition is even greater [46]. Drug interactions with benzimidazoles are increasingly reported [1,2,[47][48][49][50].…”

“…However, it has been noted that the 50% inhibitory concentration (IC 50 ) values of PPIs in inhibiting P-gp observed in vitro are higher than their expected intraluminal (intestinal) and plasma concentrations obtained after oral dosing in humans, making a drug-drug interaction at these levels unlikely. Considering that PPIs have also been shown to be CYP3A4 and CYP2C19 substrates, and that they are able to inhibit BCRP activity, under certain circumstances, for instance in poor metabolizers of CYP2C19, plasma levels of omeprazole and pantoprazole would reach the range of reported IC 50 values, thus making a clinical drug-drug interaction possible with coadministered substrate drugs for P-gp and/or BCRP [45]. In addition, several widely used drugs have been described to inhibit P-gp function, thus potentially leading to relevant drug-drug interactions.…”

Statin-Associated Polymyositis Following Omeprazole Treatment

“…Drugs of particular concern include CYP3A4 isoenzyme-dependent drugs such as macrolide antibiotics, azole antifungals, and cyclosporine, [12][13][14] drugs that interact with the glucuronidation pathway such as gemfibrozil, 12 and drugs that interact with the p-glycoprotein efflux system such as proton pump inhibitors (PPIs). 2,[15][16][17] There are many reports in the literature of an increased incidence of myopathy with use of statins combined with gemfibrozil, 18 as well as case reports of rhabdomyolysis and polymyositis associated with the use of omeprazole and other PPIs in combination with statin therapy. 2,19,20 In addition to the self-limited, toxic myopathy associated with statins, there are reports of statin-associated inflammatory myopathies including polymyositis, dermatomyositis, and necrotizing autoimmune myopathy that are characterized by elevated CK levels and proximal muscle weakness during or after statin use that persists even after discontinuation of the drug.…”

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

“…However, one case of a 3-fold increase has also been reported [38]. The above-mentioned changes are most likely to result from P-glycoprotein inhibition [39]. The effect is not the same for all proton pump inhibitors (PPIs) and seems least expressed for pantoprazole [40].…”