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

Authors
  • Ryšánek, Pavel1
  • Grus, Tomáš2
  • Lukáč, Peter2
  • Kozlík, Petr3
  • Křížek, Tomáš3
  • Pozniak, Jiří4
  • Roušarová, Jaroslava1
  • Královičová, Jana1
  • Kutinová Canová, Nikolina1
  • Boleslavská, Tereza5, 6
  • Bosák, Jan5
  • Štěpánek, František6
  • Šíma, Martin1
  • Slanař, Ondřej1
  • 1 Institute of Pharmacology, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czech Republic. , (Czechia)
  • 2 Department of Cardiovascular Surgery, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czech Republic. , (Czechia)
  • 3 Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic. , (Czechia)
  • 4 Third Department of Surgery, First Faculty of Medicine, Motol University Hospital, Charles University, Prague, Czech Republic. , (Czechia)
  • 5 Preformulation and Biopharmacy Department/Clinical Development Department, Zentiva, k.s, Prague, Czech Republic. , (Czechia)
  • 6 Department of Chemical Engineering, University of Chemistry and Technology, Prague, Czech Republic. , (Czechia)
Type
Published Article
Journal
British Journal of Pharmacology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Dec 01, 2021
Volume
178
Issue
23
Pages
4663–4674
Identifiers
DOI: 10.1111/bph.15644
PMID: 34365639
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. © 2021 The British Pharmacological Society.

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