The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model
| Autor: | Yuji Tokunaga, Kazuki Matsui, Miki Yamane, Masahisa Sugihara |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Administration
Oral Biological Availability Pharmaceutical Science Context (language use) 02 engineering and technology Pharmacology 030226 pharmacology & pharmacy Permeability Biopharmaceutics Excipients 03 medical and health sciences chemistry.chemical_compound Sugar Alcohols 0302 clinical medicine Pharmacokinetics medicine Sugar alcohol chemistry.chemical_classification 021001 nanoscience & nanotechnology Biopharmaceutics Classification System Bioavailability Intestinal Absorption Solubility chemistry Sorbitol Mannitol 0210 nano-technology medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 110:467-477 |
| ISSN: | 0022-3549 |
| Popis: | Sugar alcohols reduce oral drug bioavailability by osmotic effects, but the magnitude of these effects differs among different drugs. This study aimed to identify the drug-related critical attributes of osmotic effects and estimate the impact of a “practical” sugar alcohol dose on the pharmacokinetics of various molecules using modeling and simulation approaches. We developed a physiologically based biopharmaceutics model that considers the dose-dependent effects of sugar alcohols on the gastrointestinal physiology. The developed model captured the effects of sugar alcohols on ranitidine hydrochloride, metoprolol tartrate, theophylline, cimetidine, and lamivudine. Sensitivity analysis provided quantitative insights into the effects of sugar alcohols dependent on different drug permeability. In addition, our developed model indicated for the first time that a high systemic elimination rate is crucial for the reduction in maximum plasma concentration even for highly permeable drugs. Nonetheless, mannitol/sorbitol level of less than 400 mg had minor effects on the pharmacokinetics of the most sensitive drugs, indicating a provisional no-effect threshold dose. This mechanistic approach provides comprehensive estimation of osmotic effects on variety of drugs. Subsequently, these findings may invoke scientific discussion on the criteria for excipient changes in the context of biowaiver guidelines (e.g. biopharmaceutics classification system-based biowaiver). |
| Databáze: | OpenAIRE |
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