Browsing by Author "García Alcalde, Mauricio Andrés"

Now showing 1 - 6 of 6
  • No Thumbnail Available
    Item
    Corrigendum to Novel analytical solutions for convolution in compartmental pharmacokinetic models and application to non-bioequivalent formulations [European Journal of Pharmaceutical Sciences 202 (2024) 1–10/106892] (European Journal of Pharmaceutical Sciences (2024) 202, (S0928098724002045), (10.1016/j.ejps.2024.106892))
    (Elsevier B.V., 2024) García Alcalde, Mauricio Andrés; Gonzalez P.M.; Aceituno A.; Al-Gousous J.
    The authors regret having to inform that an error was found in the article. The statement "To the best of our knowledge, comprehensive equations for the aforementioned cases have not been reported so far" should be "While an equation for the two compartment case was derived by Humbert et al (Humbert et al, 1994), to the best of our knowledge, generalizable comprehensive equations for the aforementioned cases have not been reported so far". The authors would like to apologise for any inconvenience caused.
  • No Thumbnail Available
    Item
    Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability
    (SPRINGER/PLENUM PUBLISHERS, 2020) García Alcalde, Mauricio Andrés; Contreras Valverde, Danae Valentina; Gonzalez, Pablo M.
    PurposeMDCK cells are commonly used to assess drug permeability, but the existence of various strains merits a comparative functional study. Since metformin absorption is largely mediated by transporters and paracellular diffusion, we used it to functionally compare MDCK-wt and MDCK-II.MethodsUptake, bidirectional transport and efflux experiments were performed using different buffers, pH, and a panel of transporter inhibitors. Relative contributions to total transport in both strains were estimated.ResultsMetformin uptake into MDCK-wt was linear but saturable in MDCK-II. Uptake into MDCK-wt or -II was promoted at pH 5.4 or 8.4, respectively. Quinidine and cimetidine similarly inhibited uptake in both strains. Lopinavir (PMAT specific) at pH 5.4 or pyrimethamine (MATE specific) at pH 8.4 differentially inhibited MDCK-wt or -II, respectively. Transport at pH 7.4 was absorptive regardless of strains, but secretory (MDCK-II) or absorptive (MDCK-wt) at pH 5.4. Efflux was largely basolateral in both strains. While paracellular permeability was similar between strains, total transport was dominated by transporters in MDCK-II or paracellular diffusion in MDCK-wt.ConclusionsMetformin transport revealed functional differences between MDCK strains. Apical uptake was governed by MATE in MDCK-II or PMAT in MDCK-wt, such that metformin transport was either secretory or absorptive, respectively.
  • Thumbnail Image
    Item
    Novel analytical solutions for convolution in compartmental pharmacokinetic models and application to non-bioequivalent formulations
    (Elsevier B.V., 2024) García Alcalde, Mauricio Andrés; Gonzalez Pablo M.; Aceituno, Alexis; Al-Gousous, Josef
    © 2024 The AuthorsDeconvolution and convolution are powerful tools that allow decomposition and reconstruction, respectively, of plasma versus time profiles from input and impulse functions. While deconvolution have commonly used compartmental approaches (e.g., Wagner-Nelson or Loo-Riegelman), convolution most typically used the convolution integral which can be solved with numerical methods. In 2005, an analytical solution for one-compartment pharmacokinetic was proposed and has been widely used ever since. However, to the best of our knowledge, analytical solutions for drugs distributed in more than one compartment have not been reported yet. In this paper, analytical solutions for compartmental convolution from both original and exact Loo-Riegelman approaches were developed and evaluated for different scenarios. While convolution from original approach was slightly more precise than that from the exact Loo-Riegelman, both methods were extremely accurate for reconstruction of plasma profiles after respective deconvolutions. Nonetheless, convolution from exact Loo-Riegelman was easier to interpret and to be manipulated mathematically. In fact, convolution solutions for three and more compartments can be easily written with this approach. Finally, our convolution analytical solution was applied to predict the failure in bioequivalence for levonorgestrel, demonstrating that equations in this paper may be useful tools for pharmaceutical scientists.
  • No Thumbnail Available
    Item
    Novel food drug interaction mechanism involving acyclovir, chitosan and endogenous mucus
    (Japanese Society for the Study of Xenobiotics, 2023) García Alcalde, Mauricio Andrés; Hensler, Gonul; Al Gousous, Jozef; Pielenhofer, Jonas; Wagner, Manfred; Lennernas, Hans; Langguth, Petter
    © 2023 The Japanese Society for the Study of XenobioticsDrug absorption from drug products may be affected by pharmaceutical excipients and/or food additives through different mechanisms. Chitosan is a recognized nutraceutical, with potential as an excipient due to its permeability enhancer properties. While chitosan properties have been evaluated in in vitro and pre-clinical models, studies in humans are scarce. Unexpectedly, a controlled clinical trial showed chitosan actually reduced acyclovir bioavailability. The effect seems to be related to an interaction with gastrointestinal mucus that prevents further absorption, although more in depth research is needed to unravel the mechanism. In this paper, we propose a mechanism underlying this excipient effect. The mucus – chitosan interaction was characterized and its effect on acyclovir diffusion, permeation and bioaccessibility was investigated. Further, pharmacokinetic modeling was used to assess the clinical relevance of our findings. Results suggest that in situ coacervation between endogenous mucus and chitosan rapidly entrap 20–30% of acyclovir dissolved dose in the intestinal lumen. This local reduction of acyclovir concentration together with its short absorption window in the small intestine would explain the reduction in acyclovir Cmax and AUC. This study highlights the importance of considering mucus in any biorelevant absorption model attempting to anticipate the effect of chitosan on drug absorption.
  • No Thumbnail Available
    Item
    Poloxamer 188-Coated Ammonium Methacrylate Copolymer Nanocarriers Enhance Loperamide Permeability across Pgp-Expressing Epithelia
    (AMER CHEMICAL SOC, 2021) Catalan Figueroa, Johanna; García Alcalde, Mauricio Andrés; Cayazzo Contreras, Pilar Andrea; Boisset, Constanza B.; Gonzalez, Pablo M.; Fiedler, Jenny L.; Perez, Mariela F.; Morales, Javier O.
    Loperamide is a mu-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional mu-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.
  • Thumbnail Image
    Item
    Solubility vs Dissolution in Physiological Bicarbonate Buffer
    (Springer, 2024) Claussen, Felix; Al-Gousous, Jozef; Salehi, Niloufar; García Alcalde, Mauricio Andrés; Amidon, Gordon L.; Langguth, Peter
    Background: Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the in vivo situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds. Methods: The dissolution of an ibuprofen powder with a known particle size distribution was simulated in silico and verified experimentally in vitro at two different doses and in two different buffers (5 mM pH 6.8 bicarbonate and phosphate). Results: The results showed that there is a solubility vs. dissolution mismatch in the two buffers. This was accurately predicted by the in-house simulations based on the reversible non-equilibrium (RNE) and the Mooney models. Conclusions: The results can be explained by the existence of a relatively large gap between the initial surface pH of the drug and the bulk pH at saturation in bicarbonate but not in phosphate, which is caused by not all the interfacial reactions reaching equilibrium in bicarbonate prior to bulk saturation. This means that slurry pH measurements, while providing surface pH estimates for buffers like phosphate, are poor indicators of surface pH in the intestinal bicarbonate buffer. In addition, it showcases the importance of accounting for the H2CO3-CO2 interconversion kinetics to achieve good predictions of intestinal drug dissolution.