The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations

Franco, Valentina; Gershkovich, Pavel; Perucca, Emilio; Bialer, Meir

Abstract

For highly lipophilic drugs, passage into the intestinal lymphatic system rather than the portal vein following oral administration may represent a major alternative route of delivery into the general circulation. Increasing intestinal lymphatic transport provides an effective strategy to improve oral bioavailability when hepatic first-pass metabolism is a major rate-limiting step hampering access to the systemic circulation after oral dosing. The transfer of orally administered, highly lipid-soluble drugs to the lymphatic system is mediated by their association with chylomicrons, large intestinal lipoproteins that are assembled in the enterocytes in the presence of long-chain triglycerides or long-chain fatty acids. Due to its very high lipophilicity, cannabidiol (CBD) has physicochemical features (e.g. logP = 6.3) consistent with an oral absorption mediated at least in part by transport via the intestinal lymphatic system. CBD also undergoes extensive first-pass hepatic metabolism. Formulation changes favoring diversion of orally absorbed CBD from the portal to the lymphatic circulation pathway can result in reduced first-pass liver metabolism, enhanced oral bioavailability, and reduced intra- and intersubject variability in systemic exposure. In this manuscript, we discuss (1) evidence for CBD undergoing hepatic first-pass liver metabolism and lymphatic absorption to a clinically important extent; (2) the potential interplay between improved oral absorption, diversion of orally absorbed drug to the lymphatic system, and magnitude of presystemic elimination in the liver; and (3) strategies by which innovative chemical and/or pharmaceutical delivery systems of CBD with improved bioavailability could be developed.

Citation

Franco, V., Gershkovich, P., Perucca, E., & Bialer, M. (2020). The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations. Clinical Pharmacokinetics, 59(12), 1493-1500. https://doi.org/10.1007/s40262-020-00931-w

• Journal Article Type: Article
• Acceptance Date: Jul 31, 2020
• Online Publication Date: Aug 12, 2020
• Publication Date: 2020-12
• Deposit Date: Oct 17, 2020
• Publicly Available Date: Aug 13, 2021
• Journal: Clinical Pharmacokinetics
• Print ISSN: 0312-5963
• Electronic ISSN: 1179-1926
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 12
• Pages: 1493-1500
• DOI: https://doi.org/10.1007/s40262-020-00931-w
• Keywords: cannabidiol; lymphatic absorption; bioavailability; liver first pass-effect
• Public URL: https://nottingham-repository.worktribe.com/output/4798130
• Publisher URL: https://link.springer.com/article/10.1007%2Fs40262-020-00931-w
• Additional Information: This is a post-peer-review, pre-copyedit version of an article published in Clinical Pharmokinetics. The final authenticated version is available online at: http://dx.doi.org/10.1007/s40262-020-00931-w