No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P ‐glycoprotein (P‐gp) drug transporter

AbstractDimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P ‐glycoprotein (P‐gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experiments using CYP‐selective s ubstrates with human liver microsomes showed 50% inhibitory concentrations (IC50) of>666  µmol/L for DMF and>750  µmol/L for MMF. MMF (≤250 μmol/L; 72 hours) was not cytotoxic in cultured human hepatocyte experiments and mRNA expression data indicated no CYP induction by MMF (1‐250 µmol/L). DMF (≤6.66 mmol/L) showed moderate‐to‐high absorption (apparent permeability [Papp] ≥2.3‐29.7 x 10−6 cm/s) across a Caucasian colon adenocarcinoma (Caco‐2) cell monolayer, while MMF (≤7.38 mmol/L) demonstrated low‐to‐moderate permeability (Papp 1.2 ‐8.9 × 10−6 cm/s). DMF was not a substrate for P‐gp (net efflux ratios ≤1.22) but was a weak inhibitor of P‐gp at supratherapeutic concentrations (estimated IC50 relative to solvent control of 1.5  mmol/L; [3H]digoxin efflux in Caco ‐2 cell...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research