Biomimetic reassembled chylomicrons as novel association model for the prediction of lymphatic transportation of highly lipophilic drugs via the oral route.

Drug association with isolated natural chylomicrons (nCM) can be used to predict the lymphatic transportation potential of highly lipophilic drugs. However, the nCM model is compromised by inter-group variations in isolated nCM samples and the need to sacrifice a large quantity of animals. In this study, reassembled chylomicrons (rCM) model was set up and evaluated with respect to mimicking the drug association capacity of nCMs. A thin-film dispersion method was used to prepare rCMs, whose compositions consisted of triglycerides, phospholipids, cholesterols and derivatives in a ratio similar to that of nCMs. Partial least squares (PLS) analysis was used to evaluate the influence of molecular descriptors on drug association with CMs and establish multivariable regression equations for prediction of drug association. Chemical descriptors affecting drug association with nCM are in the sequence of hydrogen binding acceptors (HBA)>polar surface area (PSA)>solubility in long-chain triglycerides (SLCT)>logP>melting point (MP)>logD>molar volume (MV)>density>pKa>molar weight (MW)>freely rotatable bonds (FRB)>hydrogen binding donors (HBD). HBA, PSA, HBD, MP, density, pKa, FRB, and HBD were found to reduce the degree of drug association with nCM, whereas all other descriptors increased it. Sequences of chemical descriptors affecting drug association with rCM was in the order of pKa>SLCT>FRB>HBA>MW>MV>HBD>logP>MP>PSA>logD>density. However, the degree of drug association with nCMs was closely correlated to that with rCMs. Drug association with both CMs could be predicted using pre-established equations and PLS. In conclusion, rCMs could be used as substitute for nCMs in prediction of lymphatic transportation of highly lipophilic drugs.