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Validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport of drugs

P. Ryšánek, T. Grus, P. Lukáč, P. Kozlík, T. Křížek, J. Pozniak, J. Roušarová, J. Královičová, N. Kutinová Canová, T. Boleslavská, J. Bosák, F. Štěpánek, M. Šíma, O. Slanař

. 2021 ; 178 (23) : 4663-4674. [pub] 20210910

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22011780
E-zdroje Online Plný text

NLK Free Medical Journals od 1968 do Před 1 rokem
Europe PubMed Central od 1968 do Před 1 rokem
Medline Complete (EBSCOhost) od 2002-01-01 do Před 1 rokem
Wiley Free Content od 1997 do Před 1 rokem

Odkazy

PubMed 34365639
DOI 10.1111/bph.15644
Knihovny.cz E-zdroje

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.

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