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      In vitro lipolysis/microsomal metabolism approach for the prediction of oral bioavailability of BCS II drugs in lipidic formulations

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      Experimental data: In vitro lipolysis and calculation of fraction absorbed (88.17Kb)
      Intravenous and oral pharmacokinetic data collected from literature corresponding to THC and CsA (150.3Kb)
      Experimental data: Microsomal metabolism of THC and CsA, and calculation of the predicted oral bioavailability (210.0Kb)
      Publication date
      2016-08-24
      Creators
      Gershkovich, Pavel
      Benito, Paloma
      Metadata
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      Description
      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) 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.
      External URI
      • https://rdmc.nottingham.ac.uk/handle/internal/59
      DOI
      • http://doi.org/10.17639/nott.56
      Related publication DOI
      • 10.1021/acs.molpharmaceut.6b00597
      Links
      • http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.6b00597
      • http://doi.org/10.17639/nott.56
      Subjects
      • Drug carriers (Pharmacy)
      • Lipolysis
      • Drugs -- Absorption and adsorption -- Research
      • Drugs -- Absorption and adsorption -- Mathematical models
      • Drugs -- Design
      • Drugs -- Bioavailability
      • Pharmacokinetics
      • in vitro lipolysis, microsomal metabolism, IVIVC, oral bioavailability, Δ9-tetrahydrocannabinol, cyclosporine A
      • Subjects Allied to Medicine::Pharmacology, toxicology & pharmacy::Pharmacology, toxicology & pharmacy not elsewhere classified
      • R Medicine::RS Pharmacy and materia medica
      Divisions
      • University of Nottingham, UK Campus::Faculty of Science::School of Pharmacy
      Deposit date
      2016-09-20
      Data type
      Excel files with raw and processed data corresponding to the publication Benito-Gallo P., et al. Mol Pharm. (2016)
      Funders
      • Engineering & Physical Sciences Research Council
      Grant number
      • EP/I01375X/1
      Collection dates
      • 2015-2016
      Data collection method
      In vitro lipolysis, microsomal incubations, HPLC-UV, HPLC-MS/MS, Graphpad
      Resource languages
      • en
      Copyright
      • The University of Nottingham
      Publisher
      The University of Nottingham

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