Uptake of lipophilic drugs by plasma derived isolated chylomicrons: Linear correlation with intestinal lymphatic bioavailability

Association of a drug with chylomicrons in the enterocyte is an essential step in the lymphatic absorption pathway. In this article, the uptake of lipophilic compounds by chylomicrons ex vivo was compared to the corresponding intestinal lymphatic bioavailability reported in rats in order to elucidate the degree of correlation and to evaluate the utilization of this correlation as a predictive measurement of the lymphatic bioavailability potential of lipophilic drugs. Nine lipophilic compounds (Vitamin D3, Vitamin E, halofantrine, probucol, diazepam, testosterone, cyclosporin A, benzo[a]pyrene and p,p′-DDT) at a concentration of 1.75 × 10−6 M were incubated for 1 h with chylomicron emulsion separated from rat blood. A 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, P < 0.0001), whereas log P and solubility in long chain triglycerides showed only moderate correlation with lymphatic bioavailability. The linear correlation between the degree of uptake of compounds by isolated chylomicrons and intestinal lymphatic transport suggests that the two processes are governed by similar factors. Thus, the degree of association of lipophilic compounds with isolated chylomicrons can be used as a simple screening model for estimation of intestinal lymphatic transport potential of drug molecules. This approach is important in view of the practical difficulties in direct determination of the lymphatic bioavailability in vivo.