CYP Inhibition-Mediated Drug-Drug Interactions

Tihanyi, Károly; Bakk, Mónika Laura; Hellinger, Éva; Vastag, Mónika

doi:10.2174/157340810793384106

Cited by 2 publications

(1 citation statement)

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“…6 Many drugs act as inhibitors of cytochrome P450 (CYP) enzymes in vivo and thus may affect the disposition of other coadministered drugs that are also metabolized by these enzymes. 7 Consequently, inhibition of drug-metabolizing CYP enzymes is a major cause of clinically relevant drug-drug interactions (DDIs). Repeated administration of certain drugs may also induce CYP enzymes.…”

Section: Introductionmentioning

confidence: 99%

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

Aubets

Jansat

Salvà

et al. 2019

Pharmacology Res & Perspec

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Dimethylfumarate (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 substrates 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 cells). This inhibition is unlikely to be clinically relevant. MMF was not a substrate or inhibitor of P‐gp. Thus, DMF and MMF should not affect the absorption, distribution, metabolism or excretion of coadministered drugs that are CYP and P‐gp substrates.

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Section: Introductionmentioning

confidence: 99%