Gershkovich, Pavel

Hoffman, Amnon

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Simple screening methods for prediction of intestinal lymphatic transport of lipophilic drugsPavel Gershkovich and Amnon HoffmanDepartment of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, IsraelAimsTo compare the degree of uptake of lipophilic compounds by chylomicrons ex-vivo and by chylomicron-like artificial emulsionin-vitro to the corresponding intestinal lymphatic bioavailability reported in rats.To evaluate the utilization of these correlations as a predictive measurement of the lymphatic bioavailability potential of lipophilic drugs.Methods 9 lipophilic compounds (listed in Table 1) at a concentration of 1.75 × 10-6 M were incubated for 1 hour with chylomicrons separated from rat blood or with commercially available artificial chylomicron-like emulsion at pH 7.4. The lymphatic bioavailability of tested compounds reported in-vivo in rats was correlated with the degree of uptake by chylomicrons ex-vivo and by chylomicron-like emulsion in-vitro.ConclusionsBoth ex-vivo and in-vitro methods provide a good alternative to the complicated and expensive in-vivo studies of intestinal lymphatic transport of lipophilic molecules.The degree of association of lipophilic compounds with chylomicronsdepends mainly on the triglyceride content of lipoproteins, however surface apoproteins may play a considerable role in the process of uptake.05101520250 5 10 15logP% of dose absorbed into intestinal lymphatics05101520250 50 100 150 200solubility in LCT (mg/g)% of dose absorbed into intestinal lymphatics176.57 ± 8.456.79354.5p,p'-DDT16.57 ± 1.126.11252.3Benzo[a]pyrene0.53 ± 0.034853.9Paclitaxel3.65 ± 0.075.71310.4Bifonazole8.43 ± 0.215.19418.6Simvastatin60.9 ± 4.710.91519.9Probucolmiscible12.18430.7Vitamin E168.3 ± 26.39.14384.6Vitamin D347.3 ± 6.58.5500.4Halofantrine44.9 ± 15.12.921202.6CSA8.25 ± 0.303.27288.4Testosterone15.45 ± 0.412.70284.7DiazepamSolubility in LCT (mg/g)(Mean ± SD)LogPMWCompoundResultsA strong linear correlation was found between the degree of association of compounds with chylomicrons ex-vivo and the lymphatic transport reported in rats (r2 = 0.94) (Fig 2). The correlation between the degree of association of lipophilic molecules with chylomicron-like emulsion in-vitro and the lymphatic transport was slightly weaker (r2 = 0.91) (Fig 3). Physicochemical properties traditionally used to predict the intestinal lymphatic transport of lipophilic compounds have shown limited correlation with lymphatic bioavailability of tested molecules (Table 1 and Fig. 3A and 3B).Acknowledgments: This work was sponsored by the Israeli Consortium of Pharmalogica.Figure 4. Lymphatic availability of tested drugs (% of dose) vs. logP (A) and TG solubility (B).Figure 1. Schematic presentation of intestinal lymphatic absorption of lipophilic drugs. MM, mixed micelle; D, drug; LCFA, long chain fatty acids; 2-MG, 2-monoglyceride; SER, smooth endoplasmic reticulum; RER, rough endoplasmic reticulum; TGd, triglycerides rich droplet; PLp, primordial lipoprotein; CM, chylomicron. Table 1. Summary of physicochemical properties of tested drugsFigure 2. Lymphatic availability of tested drugs (% of dose) vs. degree of association of drugs with isolated CM in the ex-vivo model (% of amount).AR2 = 0.5020 R2 = 0.5545BloodLymphDLCFA2-MGLCFA2-MGDDDD DDDDDDIntestinal Lumen Enterocyte Intercellular spaceSER RERTGd PLpCMGolgiCoreexpansionMMSBIntroductionAssociation of a drug with chylomicrons in the enterocyte is the main step in the intestinal lymphatic route of absorption of lipophilic molecules (Fig. 1). Since the animal models currently used to estimate the lymphatic absorption of drugs are very difficult to perform, there is a clear need for fast and efficient models to predict the intestinal lymphatic bioavailability potential of lipophilic molecules. y = 0.2879x + 0.7187R2 = 0.939305101520250 20 40 60 80 100% association% of dose absorbed into intestinal lymphaticsy = 0.2689x + 0.2303R2 = 0.914405101520250 10 20 30 40 50 60 70 80% association% of dose absorbed into intestinal lymphaticsEx-vivo In-vitroFigure 3. Lymphatic availability of tested drugs (% of dose) vs. degree of association of drugs with artificial emulsion in the in-vitromodel (% of amount).DDThalofantrineVit Dhenz[a]pyreneVit EprobucolCSAdiazepamtestosteronehenz[a]pyreneDDTVit EhalofantrineVit DprobucolCSAdiazepamtestosteroneReferences:1. Gershkovich P. and Hoffman A. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability. Eur J Pharm Sci. 2005 Dec;26(5):394-404  

Simple screening methods for prediction of intestinal lymphatic transport of lipophilic drugs

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Simple screening methods for prediction of intestinal lymphatic transport of lipophilic drugs

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