The role of intestinal transporters and metabolism in drugs non-linear absorption kinetics

Oral drug absorption is a complex process with many physiological, physicochemical and formulation factors affecting the absorption process. Low intestinal permeability and intestinal first-pass metabolism can be major contributors to the low bioavailability as will as non-linear pharmacokinetic behavior of drugs. Furthermore, efflux and carrier-mediated transporters lined at the apical and basolateral sides of the intestine can enhance or limit the total drug absorption, and could be the reason for drugs non-linear absorption kinetic behavior. The present research applied preclinical pharmacokinetic studies and in silico simulation strategies to characterize the contribution of intestinal transporters and metabolizing enzymes in the oral bioavailability of two model compounds. The first compound is γ-tocotrienol (γ-T3), a vitamin E isoform with established anti-cancer activity. Our results showed that γ-T3 has a low permeability and negligible intestinal metabolism. In addition, the results demonstrated that γ-T3 intestinal transport is partially mediated by NPC1L1. Comparison of the oral bioavailability, dissolution, permeability, and carrier-mediated transport of γ-T3 with α-tocopherol (α-Tph) revealed that the significant higher bioavailability of α-Tph is mainly attributed to its higher permeability compared to γ-T3. Subsequent studies showed that the enhancement of intestinal permeability of γ-T3 via the application of solid lipid nanoparticles (SLN) resulted in a significant increase in its permeability and total bioavailability. The second model compound investigated was UK-343,664. In this work, the contribution of intestinal P-glycoprotein (P-gp) and CYP3A4 to the non-linear absorption kinetics of UK-343,664 in humans was investigated. Preclinical testing, in vitro and in vivo studies were conducted to obtain data required for the prediction of absorption, distribution, metabolism, and clearance of UK-343,664. The obtained data were incorporated into an in silico PBPK simulation model utilizing the ACAT model in Gastroplus™. The Km and Vmax values of intestinal CYPs determined in vitro were used directly and the corresponding values for P-gp were adjusted in the model to fit the observed human data. Our results revealed the simulation model built from the data accurately predicted the pharmacokinetic profile of UK-343,664 in dose escalating studies in humans. Furthermore, the model accurately predicted the non-linear pharmacokinetics of UK-343,664. In addition, the in silico model revealed that both P-gp and CYP3A4 are contributing to the non-linear pharmacokinetic behavior of UK-343,664.