Lymphatic Transport of Drugs after Intestinal Absorption: Impact of Drug Formulation and Physicochemical Properties
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RESEARCH PAPER
Lymphatic Transport of Drugs after Intestinal Absorption: Impact of Drug Formulation and Physicochemical Properties Pavel Ryšánek 1
&
Tomáš Grus 2 & Martin Šíma 1 & Ondřej Slanař 1
Received: 13 March 2020 / Accepted: 11 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose To provide a comprehensive and up-to-date overview focusing on the extent of lymphatic transport of drugs following intestinal absorption and to summarize available data on the impact of molecular weight, lipophilicity, formulation and prandial state. Methods Literature was searched for in vivo studies quantifying extent of lymphatic transport of drugs after enteral dosing. Pharmacokinetic data were extracted and summarized. Influence of molecular weight, log P, formulation and prandial state was analyzed using relative bioavailability via lymph (FRL) as the parameter for comparison. The methods and animal models used in the studies were also summarized. Results Pharmacokinetic data on lymphatic transport were available for 103 drugs. Significantly higher FRL [median (IQR)] was observed in advanced lipid based formulations [54.4% (52.0)] and oil solutions [38.9% (60.8)] compared to simple formulations [2.0% (27.1)], p < 0.0001 and p = 0.004, respectively. Advanced lipid based formulations also provided substantial FRL in drugs with log P < 5, which was not observed in simple formulations and oil solutions. No relation was found between FRL and molecular weight. There were 10 distinct methods used for in vivo testing of lymphatic transport after intestinal absorption so far. Conclusion Advanced lipid based formulations provide superior ability to increase lymphatic absorption in drugs of various molecular weights and in drugs with moderate to low lipophilicity.
KEY WORDS animal models . bioavailability . lipid based
* Pavel Ryšánek [email protected]
INTRODUCTION
1
Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
2
Department of Cardiovascular Surgery, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
formulations . lymphatic absorption . lymph duct cannulation
ABBREVIATIONS DTX-S-OA MCT 2-MPA-TG LCT SCT SEDDS SES SLN SMEDDS SNEDDS SNEOF SNESN TST-C5-βMe-TG
Docetaxel thioether oleate Medium chain triglycerides 1,3-dipalmitoyl-2-mycophenoloyl glycerol Long chain triglycerides Short chain triglycerides Self-emulsifying drug delivery system Self-emulsifying system Solid lipid nanoparticles Self-microemulsifying drug delivery system Self-nanoemulsifying drug delivery system Self-nanoemulsifying oily formulation Self-nanoemulsifying self-nanosuspension Testosterone triglyceride prodrug
Intestinal absorption into lymph is an active process involving transport of compounds into enterocytes and subsequent incorporation into chylomicrons and secretion into lacteals, which are blind ended structures that join to mesenteric lympha
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