High-dose etoposide formulations do not saturate intestinal P-glycoprotein:Development, stability, and pharmacokinetics in Sprague-Dawley rats
| Autor: | Lieve Dillen, René Holm, Dries Versweyveld, Jan Snoeys, Ils Pijpers, An Vermeulen, Carsten Uhd Nielsen, Ahmed A. Abdulhussein Al-Ali, Louis Sandra |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Drug Compounding Cmax Pharmaceutical Science Administration Oral Biological Availability 02 engineering and technology Dibenzocycloheptenes Poloxamer Pharmacology P-glycoprotein 030226 pharmacology & pharmacy Models Biological Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Drug Stability Oral administration medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Population pharmacokinetics Solubility Intestinal Mucosa Etoposide Zosuquidar Ethanol Povidone Sprague-Dawley rats 021001 nanoscience & nanotechnology Bioavailability chemistry Intestinal Absorption Injections Intravenous Quinolines Polyvinyls Caco-2 Cells 0210 nano-technology medicine.drug |
| Zdroj: | Al-Ali, A A A, Sandra, L, Versweyveld, D, Pijpers, I, Dillen, L, Vermeulen, A, Snoeys, J, Holm, R & Nielsen, C U 2020, ' High-dose etoposide formulations do not saturate intestinal P-glycoprotein : Development, stability, and pharmacokinetics in Sprague-Dawley rats ', International Journal of Pharmaceutics, vol. 583, 119399 . https://doi.org/10.1016/j.ijpharm.2020.119399 |
| Popis: | It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide’s solubility approximately 100 times (16 mg mL−1) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC0-∞ of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg−1), AUC0-∞ and Cmax were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg−1. A single oral dose of 20 mg kg−1 zosuquidar followed by 20 mg kg−1 oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide. |
| Databáze: | OpenAIRE |
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