Absorption Systems LP

Exton, PA, United States

Absorption Systems LP

Exton, PA, United States
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Li J.,Absorption Systems L.P. | Volpe D.A.,U.S. Food and Drug Administration | Wang Y.,Absorption Systems L.P. | Zhang W.,Absorption Systems L.P. | And 3 more authors.
Drug Metabolism and Disposition | Year: 2011

The objective of the present study was to determine the efflux transporters responsible for acid and lactone statin drug efflux using transporter knockdown Caco-2 cells. The bidirectional transport was determined in Caco-2 cell monolayers in which the expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or multidrug resistance associated protein 2 (MRP2) was knocked down by transduction with lentivirus containing human transportertargeted small hairpin RNAs (shRNAs). Cells transduced with lentivirus containing nontargeted shRNA served as the vector control. Atorvastatin, lovastatin, and rosuvastatin displayed extremely low apical-to-basolateral (A-to-B) transport, which made the Papp,A-B values too unreliable to calculate the efflux ratio. Thus, transport comparisons were performed using the B-to-A permeability (Papp,B-A) values. Presented in the order of vector control, P-gp, BCRP, and MRP2 knockdown Caco-2 cells, the Papp,B-A values (×10-6, cm/s) were 28.1 ± 1.3, 8.6 ± 2.9, 20.3 ± 1.8, and 21.5 ± 1.6 for atorvastatin; 96.1 ± 7.1, 25.3 ± 3.5, 57.3 ± 9.8, and 48.2 ± 2.3 for fluvastatin; and 14.1 ± 1.9, 4.6 ± 1.7, 5.8 ± 0.7, and 6.6 ± 1.8 for rosuvastatin, respectively. Lovastatin and simvastatin showed no efflux in the vector control or knockdown cell monolayers in either lactone or acid forms. Results indicate that atorvastatin, fluvastatin, and rosuvastatin were transported by P-gp, BCRP, and MRP2. On the other hand, neither the lactone nor the resulting acid of lovastatin and simvastatin was transported by P-gp, BCRP, or MRP2. The current study demonstrated that the transporter knockdown Caco-2 cells are useful tools for studying drug-transporter interactions and should help eliminate some of the ambiguity associated with the identification of drug-transporter interactions based on chemical inhibitors alone.

Korzekwa K.R.,Temple University | Nagar S.,Temple University | Tucker J.,Temple University | Weiskircher E.A.,Absorption Systems L.P. | And 2 more authors.
Drug Metabolism and Disposition | Year: 2012

Knowledge of free drug intracellular concentration is necessary to predict the impacts of drugs on intracellular targets. The goal of this study was to develop models to predict free intracellular drug concentrations in the presence of apical efflux transporters. The apical efflux transporter P-glycoprotein (P-gp), encoded by human gene multidrug resistance 1 (MDR1), was studied. Apparent permeabilities for 10 compounds in Madin-Darby canine kidney (MDCK) and MDR1-MDCK cell monolayers were obtained experimentally. Six of these compounds were evaluated additionally in the presence of the P-gp inhibitor cyclosporine A. A three-compartment model was developed, and passive and apical efflux clearances (CL d and CL ae, respectively) were estimated. Endogenous canine transporters also were delineated. The three-compartment model was unable to simulate experimentally observed lag times and exhibited systematic bias across the simulations. Next, a five-compartment model with explicit membrane compartments was developed. This model resulted in lower systematic errors and simulated the lag time observed experimentally. Apical efflux was modeled out of the cell or out of the membrane. The five-compartment model with apical efflux out of the membrane predicted marked differences in unbound intracellular concentrations between the apical-to-basolateral and the basolateral-to-apical directions. Upon apical drug addition, large decreases in intracellular concentrations were observed with the efflux transporter. No such difference was predicted upon basolateral drug addition. This is consistent with experimental differences in the impact of P-gp on hepatic and brain distribution and supports the hypothesis that apical efflux occurs out of the apical membrane. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.

Devalapally H.,Absorption Systems LP | Li L.,Absorption Systems LP | Perdue M.L.,FluSolutions Consulting LLC | Ostrander G.K.,Florida State University
PLoS ONE | Year: 2013

We have demonstrated that simple formulations composed of the parent drug in combination with generally regarded as safe (GRAS) permeability enhancers are capable of dramatically increasing the absolute bioavailability of zanamivir. This has the advantage of not requiring modification of the drug structure to promote absorption, thus reducing the regulatory challenges involved in conversion of an inhaled to oral route of administration of an approved drug. Absolute bioavailability increases of up to 24-fold were observed when Capmul MCM L8 (composed of mono- and diglycerides of caprylic/capric acids in glycerol) was mixed with 1.5 mg of zanamivir and administered intraduodenally to rats. Rapid uptake (tmax of 5 min) and a Cmax of over 7200 ng/mL was achieved. Variation of the drug load or amount of enhancer demonstrated a generally linear variation in absorption, indicating an ability to optimize a formulation for a desired outcome such as a targeted Cmax for enzyme saturation. No absorption enhancement was observed when the enhancer was given 2 hr prior to drug administration, indicating, in combination with the observed tmax, that absorption enhancement is temporary. This property is significant and aligns well with therapeutic applications to limit undesirable drug-drug interactions, potentially due to the presence of other poorly absorbed polar drugs. These results suggest that optimal human oral dosage forms of zanamivir should be enteric-coated gelcaps or softgels for intraduodenal release. There continues to be a strong need and market for multiple neuraminidase inhibitors for influenza treatment. Creation of orally available formulations of inhibitor drugs that are currently administered intravenously or by inhalation would provide a significant improvement in treatment of influenza. The very simple GRAS formulation components and anticipated dosage forms would require low manufacturing costs and yield enhanced convenience. These results are being utilized to design prototype dosage forms for initial human pharmacokinetic studies. © 2013 Holmes et al.

Li J.,Absorption Systems LP | Wang Y.,Absorption Systems LP | Hidalgo I.J.,Absorption Systems LP
Journal of Pharmaceutical Sciences | Year: 2013

Madin-Darby canine kidney (MDCK) cells transfected with the multidrug resistance 1 (MDR1) gene, MDR1-MDCK, are widely used as an in vitro model to classify compounds as human P-glycoprotein (hPgp) substrates or nonsubstrates. Because MDCK cells express endogenous canine Pgp (cPgp), which is prone to downregulation after transfection with hPgp, this situation could lead to false-negative classification of hPgp substrates. The aim of this study was to investigate factors that influence hPgp substrate classification in MDR1-MDCK model and to seek ways to reduce false classification. Three-compartment models were used to derive flux equations describing the drug transport processes; factors influencing hPgp substrate classification were evaluated by simulations. Pgp functionality was assessed by determining the bidirectional permeability of a series of test compounds. Expressions of hPgp and cPgp were measured by quantitative polymerase chain reaction (qPCR). Kinetic model analysis revealed that the current net flux ratio calculation for hPgp substrate classification is influenced by endogenous cPgp expression as well as hPgp-cPgp expression ratio; the effect was more pronounced in low hPgp-cPgp region and diminished in high ratio region. On the basis of kinetic considerations, this study provides a rational experimental approach and appropriate mathematical corrections to minimize the potential occurrence of false-negative classification of new molecular entities. © 2013 Wiley Periodicals, Inc.

Li J.,Absorption Systems LP | Wang Y.,Absorption Systems LP | Zhang W.,Absorption Systems LP | Huang Y.,Absorption Systems LP | And 2 more authors.
Drug Metabolism and Disposition | Year: 2012

Membrane transporters can play a clinically important role in drug absorption and disposition; Caco-2 and Madin-Darby canine kidney (MDCK) cells are the most widely used in vitro models for studying the functions of these transporters and associated drug interactions. Transport studies using these cell models are mostly focused on apical transporters, whereas basolateral drug transport processes are largely ignored. However, for some hydrophilic drugs, a basolateral uptake transporter may be required for drugs to enter cells before they can interact with apical efflux transporters. The objective of this study was to evaluate potential differences in drug transport across Caco-2 and MDCK basolateral membrane that could cause discrepancy in the identification of efflux transporter substrates and to elucidate the underlying factors that may cause such differences, using rosuvastatin as a model substrate. Bidirectional transport results in Caco-2 andbreast cancer resistance protein-MDCK cells demonstrated the necessity of an uptake transporter at the basolateral membrane for rosuvastatin. Kinetic study revealed saturable and nonsaturable processes for rosuvastatin uptake across the Caco-2 basolateral membrane, with the saturable process encompassing >75% of overall rosuvastatin basolateral uptake at concentrations below the Km (4.2 μM). Furthermore, rosuvastatin basolateral transport exhibited cis-inhibition and trans-stimulation phenomena, indicating a facilitated diffusion mechanism. This basolateral transporter appeared to be a prerequisite for rosuvastatin and perhaps for other hydrophilic substrates to interact with apical efflux transporters. Deficit of such a basolateral transporter in certain cell models may lead to false-negative results when screening drug interactions with apical efflux transporters.Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.

Nagar S.,Temple University | Tucker J.,Temple University | Weiskircher E.A.,Absorption Systems L.P. | Bhoopathy S.,Absorption Systems L.P. | And 2 more authors.
Pharmaceutical Research | Year: 2014

Purpose: With the goal of quantifying P-gp transport kinetics, Part 1 of these manuscripts evaluates different compartmental models and Part 2 applies these models to kinetic data. Methods: Models were developed to simulate the effect of apical efflux transporters on intracellular concentrations of six drugs. The effect of experimental variability on model predictions was evaluated. Several models were evaluated, and characteristics including membrane configuration, lipid content, and apical surface area (asa) were varied. Results: Passive permeabilities from MDCK-MDR1 cells in the presence of cyclosporine gave lower model errors than from MDCK control cells. Consistent with the results in Part 2, model configuration had little impact on calculated model errors. The 5-compartment model was the simplest model that reproduced experimental lag times. Lipid content and asa had minimal effect on model errors, predicted lag times, and intracellular concentrations. Including endogenous basolateral uptake activity can decrease model errors. Models with and without explicit membrane barriers differed markedly in their predicted intracellular concentrations for basolateral drug exposure. Single point data resulted in clearances similar to time course data. Conclusions: Compartmental models are useful to evaluate the impact of efflux transporters on intracellular concentrations. Whereas a 3-compartment model may be sufficient to predict the impact of transporters that efflux drugs from the cell, a 5-compartment model with explicit membranes may be required to predict intracellular concentrations when efflux occurs from the membrane. More complex models including additional compartments may be unnecessary. © 2013 Springer Science+Business Media New York.

Wang X.,Absorption Systems LP | Black L.,Absorption Systems LP
International journal of pharmaceutical compounding | Year: 2013

This ex vivo human percutaneous absorption study evaluated a set of six model drugs (ketamine hydrochloride, bupivacaine hydrochloride, diclofenac sodium, gabapentin, orphenadrine citrate, pentoxifylline) from two popular formulations for topically applied compounding preparations. The compounded preparations used in this study were Versatile cream and a reference cream. Each formulation was applied to human trunk skin mounted on Franz Diffusion Cells, 50 mg/chamber (or 28.2 mg/cm2). Serial dermal receiver solutions were collected for 48 hours. Analysis of the resultant data supports the concept that the Versatile base formulation provides improved characteristics relative to the reference base. This is of key importance where the patient does not show clinical improvement when a conventional topical delivery vehicle is used in the formulation. From the results, it is reasonable to anticipate that, relative to the reference formulation, the Versatile formulation provides enhanced transdermal delivery of some analgesic medications.

News Article | November 21, 2016
Site: www.prnewswire.com

EXTON, Pa., Nov. 21, 2016 /PRNewswire/ -- Absorption Systems, a world leader in novel test systems for drug transporters, announces the renewal of a technology licensing deal with Biogen. After years of contract testing by Absorption Systems using MDR1-MDCK cells, Biogen licensed the...

News Article | February 16, 2017
Site: www.prnewswire.com

EXTON, Pa., Feb. 16, 2017 /PRNewswire/ -- Absorption Systems, a global leader in nonclinical testing of drugs, biologics, and medical devices, is pleased to announce that its Chief Operating Officer, Sid Bhoopathy, Ph.D., has been selected as a winner of the 2017 Executive Management...

EXTON, Pa., Nov. 11, 2016 /PRNewswire/ -- Absorption Systems, a global leader in the science of translational medicine, announces the issuance of a U.S. patent for its unique In Vitro Dissolution Absorption System (IDAS2™) technology, which enables the simultaneous evaluation of drug...

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