Browsing by Author "Gonzalez, Pablo M."

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    "Development of Fixed Dose Combination Products" Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy
    (2019) Hens, Bart; Corsetti, Maura; Bermejo, Marival; Lobenberg, Raimar; Gonzalez, Pablo M.; Mitra, Amitava; Desai, Divyakant; Chilukuri, Dakshina Murthy; Aceituno, Alexis
    The gastrointestinal (GI) tract is one of the most popular and used routes of drug product administration due to the convenience for better patient compliance and reduced costs to the patient compared to other routes. However, its complex nature poses a great challenge for formulation scientists when developing more complex dosage forms such as those combining two or more drugs. Fixed dose combination (FDC) products are two or more single active ingredients combined in a single dosage form. This formulation strategy represents a novel formulation which is as safe and effective compared to every mono-product separately. A complex drug product, to be dosed through a complex route, requires judicious considerations for formulation development. Additionally, it represents a challenge from a regulatory perspective at the time of demonstrating bioequivalence (BE) for generic versions of such drug products. This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenues for successfully developing FDC products and their generic versions.
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    Inhibition Requirements of the Human Apical Sodium-Dependent Bile Acid Transporter (hASBT) Using Aminopiperidine Conjugates of glutamyl-Bile Acids
    (2009) Gonzalez, Pablo M.; Acharya, Chayan; MacKerell, Alexander D., Jr.; Polli, James E.
    Synthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.
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    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.
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    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.
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    Putative Irreversible Inhibitors of the Human Sodium-Dependent Bile Acid Transporter (hASBT; SLC10A2) Support the Role of Transmembrane Domain 7 in Substrate Binding/Translocation
    (2012) Gonzalez, Pablo M.; Hussainzada, Naissan; Swaan, Peter W.; MacKerell, Alexander D., Jr.; Polli, James E.
    To explore the involvement of transmembrane domain (TM) 7 of the human apical sodium-dependent bile acid transporter (hASBT) on bile acid (BA) binding/translocation, using two electrophilic BA derivatives as molecular probes.
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    Structural Requirements of the Human Sodium-Dependent Bile Acid Transporter (hASBT): Role of 3-and 7-OH Moieties on Binding and Translocation of Bile Acids
    (2014) Gonzalez, Pablo M.; Lagos, Carlos F.; Ward, Weslyn C.; Polli, James E.
    Bile acids (BAs) are the end products of cholesterol metabolism. One of the critical steps in their biosynthesis involves the isomerization of the 3 beta-hydroxyl (-OH) group on the cholestane ring to the common 3 alpha-configuration on BAs. BAs are actively recaptured from the small intestine by the human Apical Sodium-dependent Bile Acid Transporter (hASBT) with high affinity and capacity. Previous studies have suggested that no particular hydroxyl group on BAs is critical for binding or transport by hASBT, even though 3 beta-hydroxylated BAs were not examined. The aim of this study was to elucidate the role of the 3 alpha-OH group on BAs binding and translocation by hASBT. Ten 3 beta-hydroxylated BAs (Iso-bile acids, iBAs) were synthesized, characterized, and subjected to hASBT inhibition and uptake studies. hASBT inhibition and uptake kinetics of iBAs were compared to that of native 3 alpha-OH BAs. Glycine conjugates of native and isomeric BAs were subjected to molecular dynamics simulations to identify topological descriptors related to binding and translocation by hASBT: Iso-BAs bound to hASBT with lower affinity and exhibited reduced translocation than their respective 3 alpha-epimers. Kinetic data suggests that, in contrast to native BAs where hASBT binding is the rate-limiting step, iBAs transport was rate-limited by translocation and not binding. Remarkably, 7-dehydroxylated iBAs were not hASBT substrates, highlighting the critical role of 7-OH group on BA translocation by hASBT, especially for iBAs. Conformational analysis of gly-iBAs and native BAs identified topological features for optimal binding as: concave steroidal nucleus, 3-OH "on-" or below-steroidal plane, 7-OH below-plane, and 12-OH moiety toward-plane. Our results emphasize the relevance of the 3 alpha-OH group on BAs for proper hASBT binding and transport and revealed the critical role of 7-OH group on BA translocation, particularly in the absence of a 3 alpha-OH group. Results have implications for BA prodrug design.