Linking in Vitro Lipolysis and Microsomal Metabolism for the Quantitative Prediction of Oral Bioavailability of BCS II Drugs Administered in Lipidic Formulations

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 (F) 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 (F) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (F·F), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the "in vitro half-life" approach. The estimated F and F·F values were combined for the calculation of the predicted oral bioavailability (F). Results showed that there was a strong correlation between F and F values only when F 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.

Quantifying Hepatic Enzyme Kinetics of (-)-∆9-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, 11-OH-THC, through In Vitro Modeling

“…Indeed, when 11-OH-THC is administered i.v., 80% of the total radiolabeled dose is excreted in feces, mainly as unchanged 11-OH-THC and 8b-11-di-OH-THC (Lemberger et al, 1972). The measured THC and 11-OH-THC fu p (Table 1) using ultracentrifugation is consistent with previous reports of THC and 11-OH-THC plasma protein binding of ,0.01-0.03 (Garrett and Hunt, 1974;Widman et al, 1974;Fanali et al, 2011;Benito-Gallo et al, 2016). Adjusting the C max of THC and 11-OH-THC after inhalation or oral administration of cannabis by the fu p (Table 1), the THC and 11-OH-THC unbound C max can reach 8 and 1 nM, and 2 and 0.2 nM for inhalation and oral administration, respectively (Hunault et al, 2008;Lile et al, 2013).…”

“…The total (aggregated) THC depletion CL int was 236 ml/min per milligram (Table 4). The depletion K m and CL int of THC in HLMs has been reported to be 3.76 mM and 2.24 ml/min per milligram (tested at 1-10 mM THC), respectively, by Benito-Gallo et al (2016). The presence of BSA in our study, which led to THC fu inc of 0.04, is much smaller than the predicted fu inc by Benito-Gallo et al (2016) of 0.51, and, as such, differences in protein binding may contribute to the difference in CL int .…”

“…The formation of 11-OH-THC (Bornheim et al, 1992;Bland et al,. 2005) and depletion of THC (Benito-Gallo et al, 2016) in human liver microsomes (HLMs) have been previously reported. However, the aforementioned reports did not correct for the extensive nonspecific binding of THC and 11-OH-THC to glassware and plasticware (Garrett and Hunt, 1974).…”

Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation

“…The concentrations of CBD in rat plasma, intestinal lymph fluid, MLN homogenates, spleen homogenates, and human CM samples, as well as THC concentrations in rat plasma, intestinal lymph fluid, and human CM samples were determined using HPLC system (Waters Alliance 2695 separations module) equipped with photodiode array ultraviolet (UV) detector (Waters 996) 18 , 55 . Concentrations of THC in MLN and spleen homogenates were determined by LC-MS/MS system consisted of Quattro Ultima triple-quadrupole mass spectrometer (Waters) coupled with Agilent HPLC system (1100 Series, Agilent Technologies) as previously described for the detection of THC in microsomal samples 56 . Chromatographic conditions for the detection of CBD and THC in rat plasma, intestinal lymph fluid, MLN homogenates, spleen homogenates, and human CM samples are summarized in Supplementary Table S2 .…”

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

“…This is closely related to the complicated processes of LBDDS digestion and mixed micelles formation in the GI tract 1,2 . Due to this complexity, in vitro lipolysis or digestion systems are recommended to assess and predict the performance of LBDDS at physiological conditions [8][9][10] .…”