Validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport of drugs
| Autor: | Nikolina Kutinová Canová, J Pozniak, Ondřej Slanař, Martin Šíma, Tereza Boleslavská, Tomas Grus, Jan Bosák, Jana Královičová, Tomáš Křížek, Petr Kozlík, František Štěpánek, Pavel Ryšánek, Peter Lukáč, Jaroslava Roušarová |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Cinacalcet Abiraterone acetate Administration Oral Biological Availability Reproducibility of Results Biological Transport Cycloheximide Rats chemistry.chemical_compound Lymphatic system Intestinal Absorption Pharmaceutical Preparations chemistry Pharmacokinetics Cinacalcet Hydrochloride Oral administration Chylomicrons medicine Animals Chylomicron medicine.drug |
| Zdroj: | British Journal of Pharmacology. 178:4663-4674 |
| ISSN: | 1476-5381 0007-1188 |
| Popis: | Background and purpose Lymphatic transport of drugs after oral administration is an important mechanism for absorption of highly lipophilic compounds. Direct measurement in lymph duct cannulated animals is the gold standard method, but non-invasive cycloheximide chylomicron flow blocking method has gained popularity recently. However, concerns about its reliability have been raised. The aim of this work was to investigate the validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport using model compounds with high to very high lipophilicity, that is, abiraterone and cinacalcet. Experimental approach Series of pharmacokinetic studies were conducted with abiraterone acetate and cinacalcet hydrochloride after enteral/intravenous administration to intact, lymph duct cannulated and/or cycloheximide pre-treated rats. Key results Mean total absolute oral bioavailability of abiraterone and cinacalcet was 7.0% and 28.7%, respectively. There was a large and significant overestimation of the lymphatic transport extent by the cycloheximide method. Mean relative lymphatic bioavailability of abiraterone and cinacalcet in cycloheximide method was 28-fold and 3-fold higher than in cannulation method, respectively. Conclusion and implications Cycloheximide chylomicron flow blocking method did not provide reliable results on lymphatic absorption and substantially overestimated lymphatic transport for both molecules, that is, abiraterone and cinacalcet. This non-invasive method should not be used for the assessment of lymphatic transport and previously obtained data should be critically revised. |
| Databáze: | OpenAIRE |
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