Potential Mechanisms by Which Peceol® Increases the Gastrointestinal Absorption of Amphotericin B
Notice bibliographique
Résumé
PURPOSE: The purpose of this study was to ascertain how the incorporation of AmpB into a glyceride-rich excipient Peceol significantly increased Amphotericin B's (AmpB) gastrointestinal absorption in white male Sprague-Dawley rats. Based on preliminary studies, our working hypothesis was that incorporation of AmpB into mixed micelles composed of Peceol would significantly enhance gastro-intestinal (GI) tract absorption by increasing lymphatic drug transport and decreasing P-glycoprotein (PGP)-mediated drug efflux. METHODS: I. Lymphatic Transport STUDIES: Following an overnight fast (12-16 hr) and 48 hr postsurgery, rats were divided into two treatment groups and received a single-dose oral gavage (1 mL total volume) at 0700 h of either desoxycholate (DOC)-AmpB (5 mg AmpB/kg; n = 6 at each time point) or AmpB incorporated into 100% Peceol (Peceol-AmpB; 5 mg AmpB/kg; n = 6 at each time point). Mesenteric lymph samples were obtained prior to and at 0-4-hr, 4-6-hr, and 6-8-hr intervals post oral gavage. An equal volume of normal saline (1 mL) was administered intravenously to the animal following each blood draw to prevent fluid depletion throughout the duration of the study. Lymph was immediately harvested by centrifugation and analyzed for drug by high-performance liquid chromatography (HPLC). II. Multidrug Resistance 1 (mdr-1) STUDIES: Caco-2 cells were seeded at 10,000 cells/cm2 in T-75 flasks. When the cells reached 80% confluency, they were treated for 1 day and 7 days with 0.1% to 1.0% (v/v) Peceol or media alone (control). Following treatment, total RNA was isolated using TRIzol reagent, followed by reverse transcription into single-stranded cDNA. Polymerase chain reactions (PCR) were performed with specific primers for mdr-1. The PGP protein was determined by Western Blot Analysis. RESULTS: Mean weight of rats was not significantly different prior to and following drug administration. Similarly, kidney, liver, lung, spleen, and heart weights were not different between DOC-AmpB and Peceol-AmpB treatment group. A significantly greater amount of AmpB was transported through the mesenteric lymph duct for all the time intervals used following the administration of Peceol-AmpB treatment group compared to the administration of DOC-AmpB (suspension). A significant lower mdr-1 mRNA and PGP protein expression within Caco-2 cells was observed following 1 and 7 days treatment with Peceol 0.1% to 1.0% (v/v) compared to nontreated controls. CONCLUSIONS: Taken together, these findings suggest that Peceol increases the gastrointestinal absorption of AmpB by increasing the amount of drug that is transported through the mesenteric lymph duct and by decreasing mdr-1 mRNA and PGP protein expression, resulting in lower PGP-mediated AmpB efflux.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 source (Gemma direct ou Codex distillé), 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 ».