Human oral drugs absorption is correlated to their in vitro uptake by brush border membrane vesicles

ArticleinInternational Journal of Pharmaceutics 336(1):115-21 · May 2007with9 Reads
DOI: 10.1016/j.ijpharm.2006.11.045 · Source: PubMed
Brush border membrane vesicles (BBMV) were prepared from the rabbit small intestine for testing drug absorption potency through the enterocyte's apical membrane, which is an important compartment for drug oral absorption. Some modifications have been made to the traditional vesicle assay for adapting it to the 96-well plate format. The accumulation of 23 reference drugs was measured, and the data showed a good correlation with human oral absorption with a correlation coefficient R=0.853 (P<0.001), with the exception of a few false positive results. As the measured drug absorption may contain a membrane/protein binding component as well as drug uptake into vesicles, these two fractions can be discriminated by changing extravesicular osmolarity using different mannitol concentrations. This model can be applied for evaluating drug absorption rate/mechanisms, and helping drug selection in early drug research and development.
    • "It is well known that the oral mucosa can promote the bioavailability of a wide range of both polar and hydrophobic compounds that rapidly reach the blood circulation by-passing the GI system (Oulianova, Cheng, Huebert, & Chen, 2007). Moreover, since a large part of nutrients and non-nutrients are gastro-sensitive and/or poorly absorbed in the intestinal tract, the salivary extraction and the absorption through the oral mucosal epithelium would allow bioactive compounds to target specific tissues and organs without undergoing the potentially degrading effect of the GI digestion and/or being excreted in the feces (Oulianova et al., 2007 ). Therefore , salivary digestion is to be considered as a key step in a simulated GI digestion model for the evaluation of the bioaccessibility and bioavailability of food components and drugs. "
    [Show abstract] [Hide abstract] ABSTRACT: The in vitro bioaccessibility, bioavailability and plasma protein interaction of polyphenols from Annurca apple and other conventional cultivars were evaluated. Salivary digestion concentrated into the medium 27-35% of native apple polyphenols, suggesting the potential bioavailability through the oral mucosal epithelium of significant amounts of bioactive compounds that could be gastric sensitive and/or poorly absorbed in the intestine. Annurca flesh revealed the highest content and provided the best intestinal bioaccessibility and bioavailability of oligomeric procyanidins among all of the apple peel and flesh tested. Since 49.4% of native procyanidins were not absorbed, they are expected to accumulate in the intestinal lumen where a potential inhibition capacity of cellular cholesterol uptake could be assumed. The permeated procyanidins (6.7% of their native pattern, 12.0% of intestinal procyanidins) significantly bound (58.7%) to plasma HDLs, suggesting a major role in cholesterol metabolism. Our results would indicate Annurca apple and its potential nutraceuticals as effective in the regulation of plasma cholesterol levels.
    Article · Dec 2013
    • "Whether it is a BCS class I or III could not be decided in the absence of a better understanding of the permeability mechanism. Later, a correlation study between in vitro uptake methods and human absorption hypothesized an active Na + dependent carrier transport for lamivudine (Oulianova et al., 2007). Table 1summarizes the currently studied transporters related to lamivudine absorption. "
    [Show abstract] [Hide abstract] ABSTRACT: In order to reach the bloodstream and thus the target receptor, an orally-administered drug must first cross the intestinal barrier, which can occur via a paracellular, passive transcellular, or carrier-mediated uptake and/or efflux process (active or concentration gradient-driven). Our work aimed to explore the transport mechanism of the antiretroviral lamivudine (deoxycytidine nucleoside analogue), using a tri-compartmental strategy: in vitro, an ex vivo and an in situ method, represented by PAMPA, rat jejunum patches and rat Single Pass Intestinal Perfusion (SPIP), respectively. The determined permeability coefficients were compared with those from a published Caco-2 and MDCK study. Computational prediction of human jejunal permeability was explored, using various non-human permeability coefficients as descriptors. The ex vivo technique was performed in Franz-type diffusion cells, mounted with male Wistar rat jejunum segment patches. PAMPA was performed with an acceptor solution simulating the binding of serum proteins, an artificial membrane impregnated with egg lecithin/cholesterol and a gradient of pH between donor and acceptor solutions. The SPIP was conducted by proximal jejunum cannulation and drug perfusion in a constant flow rate of 0,2mL/min. The outcomes of our studies showed the following predicted pattern for lamivudine effective jejunal permeability: P(eff)(ex vivo A>B) > P(eff)(SPIP) > P(eff)(ex vivo B>A) > P(eff)(Caco-2) ≈ P(eff)(MDCK) ≈ P(eff)(PAMPA), strongly suggesting that this compound has carrier-mediated uptake as its dominant transport mechanism. Notwithstanding, Caco-2 cells may indicate an under-expression of uptake transporters and possibly an over-expression efflux transporters, compared to that found in the rat jejunum.
    Full-text · Article · Jan 2013
  • [Show abstract] [Hide abstract] ABSTRACT: In this study, in vitro systems were used to build 2 pharmacokinetic models that predict human oral bioavailability: the Caco-2/hepatocyte combination model and the Caco-2/hepatocyte hybrid model. Data obtained in vitro on Caco-2 cell permeability and hepatocyte clearance are routinely used to predict the fraction of absorption after oral administration and the extent of first-pass metabolism, respectively. In the Caco-2/hepatocyte combination model, results from a Caco-2 cell permeability assay and a hepatocyte clearance assay were combined to project oral bioavailability. Comparison of oral bioavailabilities predicted by the combination model and reported oral bioavailabilities in humans for 30 marketed compounds resulted in a modest correlation (r(2) = 0.66). The Caco-2/hepatocyte hybrid model, as previously reported, joins the Caco-2 and hepatocyte clearance systems into 1 assay. Improvements to the previous model were made by incorporating an elimination phase into the Caco-2/hepatocyte hybrid model. In the new hybrid model, the compound was added to a Caco-2-containing donor compartment and allowed to permeate for 2 h to a hepatocyte-containing receiver compartment. Subsequently, to mimic an elimination phase, the donor compartment was removed, and permeated compound was incubated with hepatocytes alone for an additional 3 h. The area under the concentration versus time curve (AUC) was determined for each of the same 30 marketed compounds assessed by the combination model. A linear regression analysis comparing the in vitro AUCs and reported oral bioavailabilities in humans showed a reasonable correlation (r(2) = 0.73). This study demonstrates that the Caco-2/hepatocyte hybrid model is more favorable and further proves the potential and feasibility of using in vitro screenings for the prediction of in vivo pharmacokinetics in humans.
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