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

Abstract

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.

Ivacaftor pharmacokinetics and lymphatic transport after enteral administration in rats

“…The ivacaftor lymphatic transport played only a minor role in the perspective of its general pharmacokinetics. The relative bioavailability via lymph (F RL ) of ∼5% for both the formulations is comparable to some other highly lipophilic compounds with ‘borderline’ lymphatic transport, such as abiraterone ( Rysanek et al, 2021 ), seocalcitol ( Grove et al, 2006 ), and ontazolast ( Hauss et al, 1998 ). The reason why the lymphatic transport was not significant (F RL > 10%) may lie in borderline ivacaftor lipophilicity, with the predicted log P of around 5.0.…”

“…Lymphatic transport parameters were defined and calculated as previously described ( Rysanek et al, 2020 ; Rysanek et al, 2021 ; Jelinek et al, 2022 ; Salamunova et al, 2023 ). Briefly, absolute bioavailability via lymph (F AL ) was defined as the percentage of the administered drug dose absorbed into the lymph.…”

“…As a result, ivacaftor is recommended to be taken in fed state only. While the mechanisms behind the food effect are not known, such a pronounced effect of food on bioavailability is typically observed in drugs that are lymphatically transported, such as the anti-cancer agent venetoclax ( Choo et al, 2014 ; Salem et al, 2016 ) and the calcimimetic drug cinacalcet ( Padhi et al, 2007 ; Rysanek et al, 2021 ). The presence of food, especially when rich in fat, helps to solubilize the highly lipophilic drugs within the gastrointestinal tract ( Koziolek et al, 2019 ), and additionally, the lipids play a crucial role as constituents of lipoproteins (chylomicrons), which serve as drug carriers in the intestinal lymph.…”

Preparation of Dihydromyricetin-Loaded Self-Emulsifying Drug Delivery System and Its Anti-Alcoholism Effect

“…Also, Sun M et al blocked chylomicron blood flow by intrabitoneal injection of CYC to inhibit lymphatic transport in the self-microemulsifying drug delivery system [ 44 ]. CYC, a non-specific inhibitor of protein synthesis, inhibits chylomicron secretion from epithelial cells to the chylomicron by acting on microtubules [ 45 ]. As shown in Figure 2 , DMY-SEDDS demonstrated greater absorption compared to free DMY solution during intestinal perfusion, with both the absorption rate constant (Ka) and the apparent permeability (Papp) for DMY-SEDDS (Ka = 33.60, Papp = 3.30) higher than those of DMY solution (Ka = 28.82, Papp = 2.85).…”

A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy

“…Lipophilic compounds may be absorbed across intestinal enterocytes directly into the lymphatics (Fig. 3c ; ➀) or may enter synthetic lipoprotein assembly pathways through binding affinity to the interfacial region of chylomicrons, very low-density lipoproteins (VLDLs), and high-density lipoproteins (HDLs) 38 – 41 . Following enterocyte exocytosis, drug–lipoprotein complexes are then transported across the basement membrane and traffic into lymphatics (Fig.…”