Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Pharmacodynamic Effects and Pharmacokinetics In Vivo (P1.207)
Notice bibliographique
Résumé
OBJECTIVE: To evaluate the pharmacodynamic effects and pharmacokinetics of dimethyl fumarate (DMF) and monoethyl fumarate (MEF) in vivo. BACKGROUND: Delayed-release DMF is approved in the U.S., Canada, and Australia for the treatment of multiple sclerosis. DMF is also one component of a combination product with 3 different salts of MEF, and this combination treatment is approved in Germany for psoriasis. Previous studies have characterized the in vivo properties of DMF; however MEF has been largely under explored. Characterizing potential common or distinct pharmacodynamic properties of DMF and MEF would provide important insights into the mechanisms of action for delayed-release DMF versus fixed combination products containing DMF and MEF salts. DESIGN/METHODS: Naïve mice were dosed with DMF, MEF or a combination of the two. Pharmacodynamic responses and pharmacokinetics were evaluated after a single dose and after 10 days of repeated daily dosing in multiple peripheral and CNS tissues. RESULTS: Both DMF and MEF exhibited similar pharmacokinetic profiles, however differences were noted in biodistribution; monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited a higher degree of brain penetration, whereas MEF was preferentially partitioned into kidney. Common pharmacodynamic responses were observed for DMF, MEF salts and combination treatment; however, unique responses for each treatment were also observed in all assessed tissues. Distinct pharmacodynamic responses were also observed with combination treatment, and these were not found with either individual component. CONCLUSIONS: DMF/MMF and MEF were absorbed to a similar degree after oral dosing, however there were biodistribution differences, most notably in brain and kidney. Both compounds alone or in combination were active in vivo, with some common responses and others distinct to each treatment. The data indicate that all fumaric acid esters cannot be each considered equivalent, and combinations of compounds may exert effects not observed when agents are used individually. Study Supported by: Biogen Idec Inc.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».