Abstract
Lipidic formulations (LFs) are increasingly utilized for the delivery of drugs that belong to class II of the Biopharmaceutics Classification System (BCS). The current work proposes, for the first time, the combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of BCS II drugs administered in LFs. Marinol and Neoral were selected as model LFs, and their observed oral bioavailabilities (Fobserved) were obtained from published clinical studies in humans. Two separate lipolysis buffers, differing in the level of surfactant concentrations, were used for digestion of the LFs. The predicted fraction absorbed (Fabs) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (Fg·Fh), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the "in vitro half-life" approach. The estimated Fabs and Fg·Fh values were combined for the calculation of the predicted oral bioavailability (Fpredicted). Results showed that there was a strong correlation between Fobserved and Fpredicted values only when Fabs was calculated using a buffer with surfactant concentrations closer to physiological conditions. The general accuracy of the predicted values suggests that the novel in vitro lipolysis/metabolism approach could quantitatively predict the oral bioavailability of lipophilic drugs administered in LFs.
Highlights
Current experimental and computational drug discovery techniques have exponentially increased the number of potential pharmacologically active drug candidates.[1]
The work presented proposes a novel combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of Biopharmaceutics Classification System (BCS) II drugs administered in Lipid-based formulations (LFs)
The general accuracy of the bioavailability predicted values, and the strong correlation shown with the clinical ones, suggests that the novel in vitro lipolysis/metabolism approach could satisfactory quantitatively estimate the oral bioavailability of BCS II drugs administered in LFs
Summary
Current experimental and computational drug discovery techniques have exponentially increased the number of potential pharmacologically active drug candidates.[1]. Mechanisms by which LFs may enhance the oral bioavailability of poorly water-soluble drugs include promoting drug solubilization in the intestinal milieu, delaying gastric emptying and transit time, inhibiting intestinal efflux transporters, reducing CYP-mediated gut wall metabolism, and increasing intestinal lymphatic transport of highly lipophilic compounds.[3−9] The in vitro assessment of LFs is challenging, since traditional dissolution testing lacks the flexibility to deal with the complicated interplay between lipid digestion products, drug-loading, and micellar solubilization.[10] In this regard, in vitro lipolysis is capable of mimicking the intestinal lipid digestion process and, is a suitable technique for assessing the fate of drugs administered in LFs.[11−13] Pancreatic lipase is responsible for the in vitro lipolysis process. The general assumption made by researchers working with the model is that the fraction
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