title: Intestinal lymphatic transport for drug delivery.
abstract: Intestinal lymphatic transport has been shown to be an absorptive pathway following oral administration of lipids and an increasing number of lipophilic drugs, which once absorbed, diffuse across the intestinal enterocyte and while in transit associate with secretable enterocyte lipoproteins. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, rather than the portal circulation, thus avoiding the metabolically-active liver, but still ultimately returning to the systemic circulation. Because of this parallel and potentially alternative absorptive pathway, first-pass metabolism can be reduced while increasing lymphatic drug exposure, which opens the potential for novel therapeutic modalities and allows the implementation of lipid-based drug delivery systems. This review discusses the physiological features of the lymphatics, enterocyte uptake and metabolism, links between drug transport and lipid digestion/re-acylation, experimental model (in vivo, in vitro, and in silico) of lymphatic transport, and the design of lipid- or prodrug-based drug delivery systems for enhancing lymphatic drug transport.
authors.affiliation: Pharmaceutical Sciences and Drug Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. jaime.yanez@alconlabs.com
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Yáñez
authors.forename: Stephen W J
authors.initials: SW
authors.lastname: Wang
authors.forename: Ian W
authors.initials: IW
authors.lastname: Knemeyer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wirth
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Alton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D002914:Chylomicrons / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008208:Lymphatic System / Q000378:metabolism*; D011355:Prodrugs
chemical_list: D002914:Chylomicrons; D008055:Lipids; D011355:Prodrugs