In Vitro Predictive Model for Intestinal Lymphatic Uptake: Exploration of Additional Enhancers and Inhibitors

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2024 Jun 27

PMID 38931889

Authors

Malaz Yousef

Conor OCroinin

Tyson S Le

Chulhun Park

Jieyu Zuo

Nadia Bou Chacra

Neal M Davies

Raimar Lobenberg

Affiliations

Soon will be listed here.

Abstract

Drug absorption via chylomicrons holds significant implications for both pharmacokinetics and pharmacodynamics. However, a mechanistic understanding of predicting in vivo intestinal lymphatic uptake remains largely unexplored. This study aimed to delve into the intestinal lymphatic uptake of drugs, investigating both enhancement and inhibition using various excipients through our previously established in vitro model. It also examined the applicability of the model by assessing the lymphatic uptake enhancement of a lymphotropic formulation with linoleoyl polyoxyl-6 glycerides using the same model. The model successfully differentiated among olive, sesame, and peanut oils in terms of lymphatic uptake. However, it did not distinguish between oils containing long-chain fatty acids and coconut oil. Coconut oil, known for its abundance of medium-chain fatty acids, outperformed other oils. This heightened uptake was attributed to the superior emulsification of this oil in artificial chylomicron media due to its high content of medium-chain fatty acids. Additionally, the enhanced uptake of the tested formulation with linoleoyl polyoxyl-6 glycerides underscored the practical applicability of this model in formulation optimization. Moreover, data suggested that increasing the zeta potential of Intralipid using sodium lauryl sulfate (SLS) and decreasing it using (+/-) chloroquine led to enhanced and reduced uptake in the in vitro model, respectively. These findings indicate the potential influence of the zeta potential on intestinal lymphatic uptake in this model, though further research is needed to explore the possible translation of this mechanism in vivo.

References

Phan C, Tso P . Intestinal lipid absorption and transport. Front Biosci. 2001; 6:D299-319. DOI: 10.2741/phan. View

Feng W, Qin C, Cipolla E, Lee J, Zgair A, Chu Y . Inclusion of Medium-Chain Triglyceride in Lipid-Based Formulation of Cannabidiol Facilitates Micellar Solubilization In Vitro, but In Vivo Performance Remains Superior with Pure Sesame Oil Vehicle. Pharmaceutics. 2021; 13(9). PMC: 8472830. DOI: 10.3390/pharmaceutics13091349. View

You Y, Ling P, Qu J, Bistrian B . Effects of medium-chain triglycerides, long-chain triglycerides, or 2-monododecanoin on fatty acid composition in the portal vein, intestinal lymph, and systemic circulation in rats. JPEN J Parenter Enteral Nutr. 2008; 32(2):169-75. PMC: 3202979. DOI: 10.1177/0148607108314758. View

Cifarelli V, Eichmann A . The Intestinal Lymphatic System: Functions and Metabolic Implications. Cell Mol Gastroenterol Hepatol. 2018; 7(3):503-513. PMC: 6396433. DOI: 10.1016/j.jcmgh.2018.12.002. View

Trevaskis N, Kaminskas L, Porter C . From sewer to saviour - targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov. 2015; 14(11):781-803. DOI: 10.1038/nrd4608. View

Wang T, Liu M, Portincasa P, Wang D . New insights into the molecular mechanism of intestinal fatty acid absorption. Eur J Clin Invest. 2013; 43(11):1203-23. PMC: 3996833. DOI: 10.1111/eci.12161. View

Miura S, Asakura H, Morishita T, Nagata H, Miyairi M, Tsuchiya M . Studies on the difference of lymphatic absorption between saturated and unsaturated long chain fatty acids in rats--particularly in reference with the effect of puromycin and colchicine. Keio J Med. 1979; 28(3):121-30. DOI: 10.2302/kjm.28.121. View

Briseid G, Briseid K, Kirkevold K . Increased intestinal absorption in the rat caused by sodium lauryl sulphate, and its possible relation to the cAMP system. Naunyn Schmiedebergs Arch Pharmacol. 1976; 292(2):137-44. DOI: 10.1007/BF00498584. View

Zhang Z, Lu Y, Qi J, Wu W . An update on oral drug delivery intestinal lymphatic transport. Acta Pharm Sin B. 2021; 11(8):2449-2468. PMC: 8424224. DOI: 10.1016/j.apsb.2020.12.022. View

10.

Dahan A, Hoffman A . Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur J Pharm Sci. 2005; 24(4):381-8. DOI: 10.1016/j.ejps.2004.12.006. View

11.

Punjabi M, Naha A, Shetty D, Nayak U . Lymphatic Drug Transport and Associated Drug Delivery Technologies: A Comprehensive Review. Curr Pharm Des. 2020; 27(17):1992-1998. DOI: 10.2174/1381612826999201203214247. View

12.

Caliph S, Charman W, Porter C . Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci. 2000; 89(8):1073-84. DOI: 10.1002/1520-6017(200008)89:8<1073::aid-jps12>3.0.co;2-v. View

13.

Desmarchelier C, Borel P, Lairon D, Maraninchi M, Valero R . Effect of Nutrient and Micronutrient Intake on Chylomicron Production and Postprandial Lipemia. Nutrients. 2019; 11(6). PMC: 6627366. DOI: 10.3390/nu11061299. View

14.

Morita S, Kawabe M, Nakano M, Handa T . Pluronic L81 affects the lipid particle sizes and apolipoprotein B conformation. Chem Phys Lipids. 2003; 126(1):39-48. DOI: 10.1016/s0009-3084(03)00090-2. View

15.

Hussain M . A proposed model for the assembly of chylomicrons. Atherosclerosis. 1999; 148(1):1-15. DOI: 10.1016/s0021-9150(99)00397-4. View

16.

Tso P, BALINT J, Bishop M, Rodgers J . Acute inhibition of intestinal lipid transport by Pluronic L-81 in the rat. Am J Physiol. 1981; 241(6):G487-97. DOI: 10.1152/ajpgi.1981.241.6.G487. View

17.

Hokkanen K, Tirronen A, Yla-Herttuala S . Intestinal lymphatic vessels and their role in chylomicron absorption and lipid homeostasis. Curr Opin Lipidol. 2019; 30(5):370-376. DOI: 10.1097/MOL.0000000000000626. View

18.

FIELD F, ALBRIGHT E, Mathur S . Regulation of triglyceride-rich lipoprotein secretion by fatty acids in CaCo-2 cells. J Lipid Res. 1988; 29(11):1427-37. View

19.

Gershkovich P, Hoffman A . Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability. Eur J Pharm Sci. 2005; 26(5):394-404. DOI: 10.1016/j.ejps.2005.07.011. View

20.

Demignot S, Beilstein F, Morel E . Triglyceride-rich lipoproteins and cytosolic lipid droplets in enterocytes: key players in intestinal physiology and metabolic disorders. Biochimie. 2013; 96:48-55. DOI: 10.1016/j.biochi.2013.07.009. View