Quantitative Prediction of Oral Bioavailability of a Lipophilic Antineoplastic Drug Bexarotene Administered in Lipidic Formulation Using a Combined In Vitro Lipolysis/Microsomal Metabolism Approach

Abstract

For performance assessment of the lipid-based drug delivery systems (LBDDS), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilisation processes. Much of previous research on in vitro lipolysis have mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values (Foral,predicted) of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2  1.6% and 36.2  2.6%, respectively, while the in vivo oral bioavailability (Foral) of BEX was tested as 31.5  13.4% and 31.4  5.2%, respectively. The Foral,predicted corresponded well with the Foral for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.

A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin

“…Human and rat liver microsomes were used in the experiment following previously reported methods 49,50 . Microsomes were used at 0.5 mg protein/mL and cordycepin was tested at 1 µM.…”

“…The reaction mixture was incubated in the shaking incubator at 37 °C for 30 min with sampling every 10 min. The results of intrinsic clearance and the fraction that escapes hepatic metabolism (by both well-stirred and parallel-tube models) were calculated by previously reported equations and physiological parameters 50–52 . The experiments were performed in triplicates.…”

Predicting Intestinal and Hepatic First-Pass Metabolism of Orally Administered Testosterone Undecanoate

“…Stability studies were performed using human liver microsomes. The in vitro intrinsic clearance (Cl int , mL/min/mg protein) was calculated using the in vitro half-life (t 1/2 inv ) of TU depletion in human liver microsomes according to Equation (1) [17,18].…”

A Novel Co-Crystal of Bexarotene and Ligustrazine Improves Pharmacokinetics and Tissue Distribution of Bexarotene in SD Rats

“…BEX (5 mg/kg) and oral BEX (30 mg/kg) or 2BEX-LIG (equivalent to 30 mg/kg BEX) are presented in Figure 8 , and the pharmacokinetic parameters are listed in Table 4 . C max of BEX in the plasma sample of rats administered 2BEX-LIG was roughly 2-fold higher than those of rats administrated with BEX, and T max was delayed from 7.33 h to 9.58 h, while MRT did not significantly change from 11 to 11.33 h. AUC (0-∞) of BEX in rats administrated 2BEX-LIG was significantly improved from 7.30 × 10 3 to 1.31 × 10 4 μg/L·h, and absolute bioavailability of BEX about 2-fold in rats, which was similar to the result of the BEX nanocrystal enhanced the bioavailability of BEX, but it did not need to select optimal stabilizers, which were essential to prepare the BEX nanocrystal [ 25 , 31 ]. Besides, 2BEX-LIG enhancing the absolute bioavailability of BEX could be explained by the different characteristics of intermolecular arrangement order [ 62 ] between BEX and 2BEX-LIG which further improved the dissolution and absorption in intestine.…”

“…The poor solubility of BEX led to low bioavailability in rats, which was about 18.13% in a previous study [ 24 ]. Although BEX was formulated into linoleic acid or sunflower oil [ 25 ] to improve the physicochemical properties, the oral bioavailability of BEX in rats was still quite low, at 31.5% and 31.4%, respectively. However, due to the poor water solubility and bioavailability, the clinical practice of BEX is severely restricted [ 26 ].…”