Pharmacokinetic drug–drug interactions with methotrexate in oncology

Abstract

Methotrexate is an antifolate agent used in the treatment of various cancers and some autoimmune diseases. In oncology, methotrexate is frequently administered at a high dose (>1 g/m(2)) and comes with various procedures to reduce the occurrence of toxicity and particularly to ensure optimal renal elimination. Drug-drug interactions involving methotrexate are the origin of severe side effects owing to delayed elimination of the antifolate and, more rarely, of decreased efficacy in relation to suboptimal exposure. Most of these interactions are driven by membrane drug transporters whose activity/expression can be inhibited by the interacting medication. In the last 10 years, research on drug transporters has permitted retrospective identification of the molecular mechanisms underlying drug-drug interactions with methotrexate. This article summarizes reported drug-drug interactions involving methotrexate in clinical oncology with reference to the role of drug transporters that control the disposition of the antifolate agent.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

“…Chioukh et al [11] reported that lansoprazole inhibited the transport of methotrexate (an antifolate drug) via hOAT3. Drug interactions between methotrexate and PPIs, including lansoprazole, have been reported in various clinical trials [12-14]. Similarly, our recent study demonstrated that lansoprazole competitively inhibited hOAT3-mediated transport of pemetrexed, which has a structure and pharmacokinetics similar to those of methotrexate [15].…”

“…In contrast, the ratio of unbound C max to IC 50 value of (S)-lansoprazole against hOAT3 in PM of CYP2C19 was ≥0.1, suggesting a clinical interaction between (S)-lansoprazole and hOAT3 substrates in PM (data not shown). Indeed, the delayed elimination of methotrexate (hOAT3 substrate) was observed in patients receiving racemic lansoprazole [12-14, 36]. Miura et al [38] demonstrated that the pharmacokinetics of (S)-lansoprazole were more intensely affected by ­ CYP2C19 polymorphism than those of (R)-lansoprazole, suggesting that (S)-lansoprazole is responsible for individual variations of lansoprazole-induced drug interactions associated with hOAT3.…”

Personalizing chemotherapy dosing using pharmacological methods

“…It also presents high PK variability, in particular its drug clearance, which ranges from 40 to 400 mL/min [69]. Moreover, methotrexate PK variability has been linked to both efficacy and toxicity, including myelosuppression, hepatotoxicity, and renal toxicity [70].…”

Mécanismes des interactions pharmacocinétiques impliquant les agents anticancéreux oraux

“…L'absorption dépend des caractéristiques physico-chimiques du médicament qui vont affecter sa solubilité et sa stabilité dans le tube digestif, d'une part, et sa perméabilité à la membrane intestinale, d'autre part [3]. En cas d'augmentation de la dose, ces propriétés peuvent limiter l'absorption par saturation de la solubilisation ou de la perméation (cas du lapatinib ou du méthotrexate oral) [4,5]. La fraction absorbée du médicament (ou biodisponibilité qui correspond à la quantité disponible pour l'action pharmacologique) est également dépendante d'une éventuelle perte par métabolisme digestif et hépatique présystémique (appelé effet de premier passage) [3].…”