Suspicion of Drug-Drug Interaction between High-Dose Methotrexate and Proton Pump Inhibitors: A Case Report – Should the Practice Be Changed?

Abstract

We report a case of a potential drug-drug interaction in a woman treated by a first injection of high-dose methotrexate for a T-lymphoblastic lymphoma. Valaciclovir, fluoxetine and pantoprazole were given concomitantly. A methotrexate overdosage was shown at 36 h after infusion associated with a severe renal failure. Alkaline hyperhydration, folinic acid and carboxypeptidase G2 were given. Prescription analyses by pharmacists and literature research have permitted us to suggest that a drug-drug interaction between methotrexate and proton pump inhibitors (PPI) was responsible for this renal failure. Several mechanisms of interaction were suggested and might be related to the inhibition of renal methotrexate transporters by PPI, an increase in the methotrexate efflux to the blood by an upregulation of multidrug resistance protein 3 by PPI or genetic polymorphisms. This case shows that pharmacists can help physicians to optimize patient treatment: they consensually decided on the systematic discontinuation of PPI or a switch to ranitidine when patients were treated by high-dose methotrexate.

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

“…More recently, several BCRP substrate drugs were shown to significantly interact with other drugs that are BCRP inhibitors in humans, implying that BCRP may play a crucial role in such DDIs. These DDIs include the interactions between atorvastatin and tipranavir/ritonavir (153), rosuvastatin and tipranavir/ritonavir (153), rosuvastatin and atazanavir/ ritonavir (154), rosuvastatin and lopinavir/ritonavir (155), rosuvastatin and cyclosporine (156), rosuvastatin and eltrombopag (157,158), rosuvastatin and GSK1292263 (159), simvastatin and GSK1292263 (159), sulfasalazine and curcumin (160), and methotrexate and the proton pump inhibitor omeprazole, lansoprazole, or pantoprazole (161,162). Such DDIs all resulted in at least 20% significant increase in plasma AUC, C max , and/or clearance of the BCRP substrate drugs particularly rosuvastatin.…”

Potential Interactions with Anticancer Agents: A Cross-Sectional Study

“…For example, fluorouracil can increase the anticoagulant effect of coumarins [3,9], cotrimoxazole or pantoprazole may increase the toxicity of methotrexate [8,12], and even fatal cases of fluorouracil or methotrexate toxicity have been reported in patients who receive sorivudine or non - steroidal anti-inflammatory drugs (NSAIDs), respectively [3,8]. Interactions can also occur with food, alcohol or herbs.…”

Six stabs in the back of proton pump inhibitors

“…Его биотрансформация происходит в печени, при этом большая часть неизмененного препарата и его главного метаболита -7-гидроксиметотрексата (7-ОН-МТ) -выводится почками [46][47][48].…”

“…В последние годы в качестве одного из важнейших ме-ханизмов трансмембранного перемещения молекулы МТ обсуждается его взаимодействие с особым лигандом -белком резистентности рака молочной железы (БРРМЖ). Как показывают данные ряда исследований, этот механизм может нарушаться под влиянием ИПП [46][47][48].…”

“…В медицинской литературе имеется описание нескольких случаев тяжелых осложнений (в пер-вую очередь, почечной недостаточности), развившихся при использовании высоких доз МТ у лиц, одновременно получавших ИПП [48,49].…”