[PMID]: | 27173987 |
[Au] Autor: | Fasinu P; Choonara YE; Kumar P; du Toit LC; Bijukumar D; Khan RA; Pillay V |
[Ad] Endereço: | Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa. |
[Ti] Título: | Enhancement of the Oral Bioavailability of Felodipine Employing 8-Arm-Poly(Ethylene Glycol): In Vivo, In Vitro and In Silico Evaluation. |
[So] Source: | AAPS PharmSciTech;18(3):617-628, 2017 Apr. |
[Is] ISSN: | 1530-9932 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Poor oral bioavailability is the single most important challenge in drug delivery. Prominent among the factors responsible for this is metabolic activity of the intestinal and hepatic cytochrome P450 (CYP450) enzymes. In preliminary studies, it was demonstrated that 8-arm-PEG was able to inhibit the felodipine metabolism. Therefore, this report investigated the oral bioavailability-enhancing property of 8-arm-PEG employing detailed in vitro, in vivo, and in silico evaluations. The in vitro metabolism of felodipine by cytochrome P450 3A4-expressed human liver microsomes (HLM) was optimized yielding a typical Michaelis-Menten plot through the application of Enzyme Kinetic Module software from where the enzyme kinetic parameters were determined. In vitro investigation of 8-arm-poly(ethylene glycol) against CYP3A4-catalyzed felodipine metabolism employing human liver microsomes compared closely with naringenin, a typical grapefruit flavonoid, yielding IC values of 7.22 and 121.97 µM, respectively. The investigated potential of 8-arm-poly(ethylene glycol) in oral drug delivery yielded satisfactory in vitro drug release results. The in vivo studies of the effects of 8-arm-poly(ethylene glycol) on the oral bioavailability of felodipine as performed in the Large White pig model showed a >100% increase in plasma felodipine levels compared to controls, with no apparent effect on systemic felodipine clearance. The outcome of this research presents a novel CYP3A4 inhibitor, 8-arm-poly(ethylene glycol) for oral bioavailability enhancement. |
[Mh] Termos MeSH primário: |
Etilenoglicóis/química Felodipino/química Felodipino/metabolismo
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[Mh] Termos MeSH secundário: |
Administração Oral Adulto Idoso Animais Disponibilidade Biológica Citocromo P-450 CYP3A Sistemas de Liberação de Medicamentos/métodos Feminino Flavanonas/metabolismo Flavonoides/metabolismo Seres Humanos Cinética Fígado/metabolismo Masculino Microssomos Hepáticos/metabolismo Meia-Idade Suínos Adulto Jovem
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Ethylene Glycols); 0 (Flavanones); 0 (Flavonoids); EC 1.14.14.1 (Cytochrome P-450 CYP3A); HN5425SBF2 (naringenin); OL961R6O2C (Felodipine) |
[Em] Mês de entrada: | 1707 |
[Cu] Atualização por classe: | 170713 |
[Lr] Data última revisão:
| 170713 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 160514 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1208/s12249-016-0545-8 |
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