Publications by authors named "Matthew Harwood"

16 Publications

  • Page 1 of 1

68Ga DOTATATE PET/CT imaging of Currarino syndrome with neuroendocrine tumor.

Jpn J Clin Oncol 2021 Feb 24. Epub 2021 Feb 24.

Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ, USA.

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http://dx.doi.org/10.1093/jjco/hyab020DOI Listing
February 2021

Quantification of Proteins Involved in Intestinal Epithelial Handling of Xenobiotics.

Clin Pharmacol Ther 2021 Apr 5;109(4):1136-1146. Epub 2020 Dec 5.

Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.

The intestinal epithelium represents a natural barrier against harmful xenobiotics, while facilitating the uptake of nutrients and other substances. Understanding the interaction of chemicals with constituents of the intestinal epithelium and their fate in the body requires quantitative measurement of relevant proteins in in vitro systems and intestinal epithelium. Recent studies have highlighted the mismatch between messenger RNA (mRNA) and protein abundance for several drug-metabolizing enzymes and transporters in the highly dynamic environment of the intestinal epithelium; mRNA abundances cannot therefore be used as a proxy for protein abundances in the gut, necessitating direct measurements. The objective was to determine the expression of a wide range proteins pertinent to metabolism and disposition of chemicals and nutrients in the intestinal epithelium. Ileum and jejunum biopsy specimens were obtained from 16 patients undergoing gastrointestinal elective surgery. Mucosal fractions were prepared and analyzed using targeted and global proteomic approaches. A total of 29 enzymes, 32 transporters, 6 tight junction proteins, 2 adhesion proteins, 1 alkaline phosphatase, 1 thioredoxin, 5 markers, and 1 regulatory protein were quantified-60 for the first time. The global proteomic method identified a further 5,222 proteins, which are retained as an open database for interested parties to explore. This study significantly expands our knowledge of a wide array of proteins important for xenobiotic handling in the intestinal epithelium. Quantitative systems biology models will benefit from the novel systems data generated in the present study and the translation path offered for in vitro to in vivo translation.
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http://dx.doi.org/10.1002/cpt.2097DOI Listing
April 2021

Characteristics and outcome of patients with relapsed/refractory Hodgkin lymphoma following front-line escalated BEACOPP-based chemotherapy: a report from the Australasian Lymphoma Alliance.

Leuk Lymphoma 2020 12 28;61(14):3412-3416. Epub 2020 Aug 28.

Gold Coast University Hospital, Southport, Australia.

The optimal management of the small number of patients who experience early failure of eBEACOPP in Hodgkin lymphoma (HL) is unclear. We identified 12 patients with HL who progressed within 12 months of the front-line therapy between January 2010 and July 2019. Median time of first progression following diagnosis was 7 months (range 2.1-13.2). Nine patients proceeded to stem cell therapy following salvage therapy (8 autografts, 1 allograft). Seven patients received novel therapy after relapse, of these, 6 were alive at census, versus 2 out of 5 of those who had standard therapy alone. At the end of follow up (median 22 months), 4 were deceased from progressive disease, 6 were in complete remission and 2 in partial remission on continuing therapy. The outcome of patients with primary refractory HL to eBEACOPP therapy is better than expected and the use of a novel agents after relapse may be a contributing factor.
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http://dx.doi.org/10.1080/10428194.2020.1811273DOI Listing
December 2020

Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine.

Drug Metab Dispos 2020 04 20;48(4):245-254. Epub 2020 Jan 20.

Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.C., Z.M.A.-M., B.A., J.B., A.R.-H.); Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (S.G., P.J.D., G.C., G.W.); and Certara UK Limited (Simcyp Division), Sheffield, United Kingdom (M.D.H., A.R.-H.).

The levels of drug-metabolizing enzymes (DMEs) and transporter proteins in the human intestine are pertinent to determine oral drug bioavailability. Despite the paucity of reports on such measurements, it is well recognized that these values are essential for translating in vitro data on drug metabolism and transport to predict drug disposition in gut wall. In the current study, clinically relevant DMEs [cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT)] and drug transporters were quantified in total mucosal protein preparations from the human jejunum ( = 4) and ileum ( = 12) using quantification concatemer-based targeted proteomics. In contrast to previous reports, UGT2B15 and organic anion-transporting polypeptide 1 (OATP1A2) were quantifiable in our samples. Overall, no significant disparities in protein expression were observed between jejunum and ileum. Relative mRNA expression for drug transporters did not correlate with the abundance of their cognate protein, except for P-glycoprotein 1 (P-gp) and organic solute transporter subunit alpha (OST-), highlighting the limitations of RNA as a surrogate for protein expression in dynamic tissues with high turnover. Intercorrelations were found within P450 [2C9-2C19 ( = 0.002, = 0.63), 2C9-2J2 ( = 0.004, = 0.40), 2D6-2J2 ( = 0.002, = 0.50)] and UGT [1A1-2B7 ( = 0.02, = 0.87)] family of enzymes. There were also correlations between P-gp and several other proteins [OST- ( < 0.0001, = 0.77), UGT1A6 ( = 0.009, = 0.38), and CYP3A4 ( = 0.007, = 0.30)]. Incorporating such correlations into building virtual populations is crucial for obtaining plausible characteristics of simulated individuals. SIGNIFICANCE STATEMENT: A number of drug transporters were quantified for the first time in this study. Several intercorrelations of protein abundance were reported. mRNA expression levels proved to be a poor reflection of differences between individuals regarding the level of protein expression in gut. The reported abundance of drug-metabolizing enzymes and transporters and their intercorrelations will contribute to better predictions of oral drug bioavailability and drug-drug interactions by linking in vitro observations to potential outcomes through physiologically based pharmacokinetic models.
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http://dx.doi.org/10.1124/dmd.119.089656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076527PMC
April 2020

Trends in myeloma relative survival in Queensland by treatment era, age, place of residence, and socioeconomic status.

Leuk Lymphoma 2020 03 14;61(3):721-727. Epub 2019 Nov 14.

Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia.

Relative survival (RS) in myeloma has improved in younger but not older patients (≥80 years) with treatment advances. Whether place of residence or socioeconomic status (SES) affect RS is unknown. We used the Queensland cancer registry to calculate the five-year RS of myeloma patients diagnosed between 1982 and 2014. This period was divided into three eras: (1) 1982-1995 chemotherapy alone; (2) 1996-2007 autologous stem cell transplantation; (3) 2008-2014 novel agents (proteasome inhibitors and IMIDs). 6025 patients were diagnosed from 1982 to 2014. RS improved across eras: (1) 30% vs. (2) 43% vs. (3) 53% ( < .001 (2) vs. (1);  < .001 (3) vs. (2)). RS improved across all age groups, including patients ≥80 years. Patients with disadvantaged SES (39% vs. affluent 46%;  < .001) and rural patients (40% vs. urban 45%;  < .001) had an inferior RS. RS has improved across all ages with treatment advances.
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http://dx.doi.org/10.1080/10428194.2019.1688322DOI Listing
March 2020

The Regional-Specific Relative and Absolute Expression of Gut Transporters in Adult Caucasians: A Meta-Analysis.

Drug Metab Dispos 2019 08 10;47(8):854-864. Epub 2019 May 10.

Certara UK Ltd., Simcyp Division, Sheffield, United Kingdom.

The aim of this study was to derive region-specific transporter expression data suitable for in vitro-to-in vivo extrapolation (IVIVE) within a physiologically based pharmacokinetic (PBPK) modeling framework. A meta-analysis was performed whereby literary sources reporting region-specific transporter expression obtained via absolute and relative quantification approaches were considered in healthy adult Caucasian individuals. Furthermore, intestinal total membrane protein yield was calculated to enable mechanistic IVIVE via absolute transporter abundances. Where required, authors were contacted for additional information. A refined database was constructed where samples were excluded based on quantification in, non-Caucasian subjects, disease tissue, subjects <18 years old, duplicated samples, non-total membrane matrix, pooled matrices, or cDNA. Demographic data were collected where available. The weighted and geometric mean, coefficient of variation, and between-study homogeneity was calculated in each of eight gut segments (duodenum, two jejunum, four ileum, and colon) for 16 transporters. Expression data were normalized to that in the proximal jejunum. From a total of 47 articles, the final database consisted of 2238 measurements for 16 transporters. The solute carrier peptide transporter 1 (PepT1) showed the highest jejunal abundance, while multidrug resistance-associated protein (MRP) 2 was the highest abundance ATP-binding cassette transporter. Transporters displaying significant region-specific expression included the ileal bile acid transporter, which showed 18-fold greater terminal ileum expression compared with the proximal jejunum, while MRP3, organic cation transporter type 1 (OCTN1), and OCT1 showed >2-fold higher expression in other regions compared with the proximal jejunum. This is the first systematic analysis incorporating absolute quantification methodology to determine region-specific intestinal transporter expression. It is expected to be beneficial for mechanistic transporter IVIVE in healthy adult Caucasians. SIGNIFICANCE STATEMENT: Given the burgeoning reports of absolute transporter abundances in the human intestine, the incorporation of such information into mechanistic IVIVE-PBPK models could offer a distinct advantage in facilitating the robust assessment of the impact of gut transporters on drug disposition. The systematic and formal assessment via a literature meta-analysis described herein, enables assignment of the regional-specific expression, absolute transporter abundances, interindividual variability, and other associated scaling factors to healthy Caucasian populations within PBPK models. The resulting values are available to incorporate into PBPK models, and offer a verifiable account describing intestinal transporter expression within PBPK models for persons wishing to utilize them. Furthermore, these data facilitate the development of appropriate IVIVE scaling strategies using absolute transporter abundances.
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http://dx.doi.org/10.1124/dmd.119.086959DOI Listing
August 2019

The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

J Pharm Sci 2017 09 8;106(9):2826-2838. Epub 2017 May 8.

Simcyp Ltd. (a Certara Company), Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK.

The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed. Overall, 178 system parameter values for the model are provided. This study also highlights gaps in available system data required for strain-specific rat PBPK model development. The model's functionality and performance were assessed using previous literature-sourced in vitro properties for diazepam, metoprolol, and midazolam. The results of simulations were compared against observed pharmacokinetic rat data. Predicted and observed concentration profiles in 10 tissues for diazepam after a single intravenous (i.v.) dose making use of either observed i.v. clearance (CL) or in vitro hepatocyte intrinsic clearance (CL) for simulations generally led to good predictions in various tissue compartments. Overall, all i.v. plasma concentration profiles were successfully predicted. However, there were challenges in predicting oral plasma concentration profiles for metoprolol and midazolam, and the potential reasons and according solutions are discussed.
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http://dx.doi.org/10.1016/j.xphs.2017.05.003DOI Listing
September 2017

Abundance of Hepatic Transporters in Caucasians: A Meta-Analysis.

Drug Metab Dispos 2016 10 4;44(10):1550-61. Epub 2016 Aug 4.

Simcyp Limited (a Certara Company), Sheffield, United Kingdom

This study aimed to derive quantitative abundance values for key hepatic transporters suitable for in vitro-in vivo extrapolation within a physiologically based pharmacokinetic modeling framework. A meta-analysis was performed whereby data on abundance measurements, sample preparation methods, and donor demography were collated from the literature. To define values for a healthy Caucasian population, a subdatabase was created whereby exclusion criteria were applied to remove samples from non-Caucasian individuals, those with underlying disease, or those with subcellular fractions other than crude membrane. Where a clinically relevant active genotype was known, only samples from individuals with an extensive transporter phenotype were included. Authors were contacted directly when additional information was required. After removing duplicated samples, the weighted mean, geometric mean, standard deviation, coefficient of variation, and between-study homogeneity of transporter abundances were determined. From the complete database containing 24 transporters, suitable abundance data were available for 11 hepatic transporters from nine studies after exclusion criteria were applied. Organic anion transporting polypeptides OATP1B1 and OATP1B3 showed the highest population abundance in healthy adult Caucasians. For several transporters, the variability in abundance was reduced significantly once the exclusion criteria were applied. The highest variability was observed for OATP1B3 > OATP1B1 > multidrug resistance protein 2 > multidrug resistance gene 1. No relationship was found between transporter expression and donor age. To our knowledge, this study provides the first in-depth analysis of current quantitative abundance data for a wide range of hepatic transporters, with the aim of using these data for in vitro-in vivo extrapolation, and highlights the significance of investigating the background of tissue(s) used in quantitative transporter proteomic studies. Similar studies are now warranted for other ethnicities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034697PMC
http://dx.doi.org/10.1124/dmd.116.071183DOI Listing
October 2016

Breast Cancer Resistance Protein Abundance, but Not mRNA Expression, Correlates With Estrone-3-Sulfate Transport in Caco-2.

J Pharm Sci 2016 Apr 4;105(4):1370-5. Epub 2016 Mar 4.

Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford M6 8HD, UK.

Transporter mRNA and protein expression data are used to extrapolate in vitro transporter kinetics to in vivo drug disposition predictions. Breast cancer resistance protein (BCRP) possesses broad substrate specificity; therefore, understanding BCRP expression-activity relationships are necessary for the translation to in vivo. Bidirectional transport of estrone-3-sulfate (E-3-S), a BCRP probe, was evaluated with respect to relative BCRP mRNA expression and absolute protein abundance in 10- and 29-day cultured Caco-2 cells. BCRP mRNA expression was quantified by real-time PCR against a housekeeper gene, Cyclophilin A. The BCRP protein abundance in total membrane fractions was quantified by targeted proteomics, and [(3)H]-E-3-S bidirectional transport was determined in the presence or absence of Ko143, a potent BCRP inhibitor. BCRP mRNA expression was 1.5-fold higher in 29- versus 10-day cultured cells (n = 3), whereas a 2.4-fold lower (p < 0.001) BCRP protein abundance was observed in 29- versus 10-day cultured cells (1.28 ± 0.33 and 3.06 ± 0.22 fmol/μg protein, n = 6, respectively). This correlated to a 2.45-fold lower (p < 0.01) efflux ratio for E-3-S in 29- versus 10-day cultured cells (8.97 ± 2.51 and 3.32 ± 0.66, n = 6, respectively). Caco-2 cell BCRP protein abundance, but not mRNA levels, correlates with BCRP activity, suggesting that extrapolation strategies incorporating BCRP protein abundance-activity relationships may be more successful.
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http://dx.doi.org/10.1016/j.xphs.2016.01.018DOI Listing
April 2016

In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition.

Drug Metab Dispos 2016 Mar 3;44(3):476-80. Epub 2016 Feb 3.

Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).

Relative expression factors (REFs) are used to scale in vitro transporter kinetic data via in vitro-in vivo extrapolation linked to physiologically based pharmacokinetic (IVIVE-PBPK) models to clinical observations. Primarily two techniques to quantify transporter protein expression are available, immunoblotting and liquid chromatography-tandem mass spectrometry. Literature-collated REFs ranged from 0.4 to 5.1 and 1.1 to 90 for intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. The impact of using human jejunum-Caco-2 REFs for P-gp (REFiP-gp) and BCRP (REFiBCRP), generated from the same samples and using different proteomic methodologies from independent laboratories, on PBPK outcomes was assessed. A 5-fold decrease in REFiP-gp for a single oral dose of digoxin resulted in a 1.19- and 1.31-fold higher plasma area under the curve and Cmax, respectively. All generated REFiP-gp values led to simulated digoxin Cmax values within observed ranges; however, combining kinetic data generated from a different laboratory with the 5-fold lower REFiP-gp could not recover a digoxin-rifampicin drug-drug interaction, emphasizing the necessity to obtain transporter-specific kinetic estimates and REFs from the same in vitro system. For a theoretical BCRP compound, with absorption taking place primarily in the jejunum, a decrease in the REFiBCRP from 2.22 (University of Manchester) to 1.11 (Bertin Pharma) promoted proximal intestinal absorption while delaying tmax 1.44-fold. Laboratory-specific differences in REF may lead to different IVIVE-PBPK outcomes. To understand the mechanisms underlying projected pharmacokinetic liabilities, it is important to assess the potential impact of bias on the generation of REFs on an interindividual basis within a target population.
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http://dx.doi.org/10.1124/dmd.115.067777DOI Listing
March 2016

In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-Glycoprotein and Breast Cancer Resistance Protein: Part I: A Cross-Laboratory Comparison of Transporter-Protein Abundances and Relative Expression Factors in Human Intestine and Caco-2 Cells.

Drug Metab Dispos 2016 Mar 2;44(3):297-307. Epub 2015 Dec 2.

Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R-H.); Simcyp Limited (a Certara Company), Sheffield (M.D.H., S.N., A.R-H.), United Kingdom.

Over the last 5 years the quantification of transporter-protein absolute abundances has dramatically increased in parallel to the expanded use of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetics (PBPK)-linked models, for decision-making in pharmaceutical company drug development pipelines and regulatory submissions. Although several research groups have developed laboratory-specific proteomic workflows, it is unclear if the large range of reported variability is founded on true interindividual variability or experimental variability resulting from sample preparation or the proteomic methodology used. To assess the potential for methodological bias on end-point abundance quantification, two independent laboratories, the University of Manchester (UoM) and Bertin Pharma (BPh), employing different proteomic workflows, quantified the absolute abundances of Na/K-ATPase, P-gp, and breast cancer resistance protein (BCRP) in the same set of biologic samples from human intestinal and Caco-2 cell membranes. Across all samples, P-gp abundances were significantly correlated (P = 0.04, Rs = 0.72) with a 2.4-fold higher abundance (P = 0.001) generated at UoM compared with BPh. There was a systematically higher BCRP abundance in Caco-2 cell samples quantified by BPh compared with UoM, but not in human intestinal samples. Consequently, a similar intestinal relative expression factor (REF), derived from distal jejunum and Caco-2 monolayer samples, between laboratories was found for P-gp. However, a 2-fold higher intestinal REF was generated by UoM (2.22) versus BPh (1.11). We demonstrate that differences in absolute protein abundance are evident between laboratories and they probably result from laboratory-specific methodologies relating to peptide choice.
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http://dx.doi.org/10.1124/dmd.115.067371DOI Listing
March 2016

Lost in centrifugation: accounting for transporter protein losses in quantitative targeted absolute proteomics.

Drug Metab Dispos 2014 Oct 24;42(10):1766-72. Epub 2014 Jul 24.

Gut Barrier Group, Inflammation & Repair, University of Manchester, Salford Royal NHS Trust, Salford (M.D.H., G.W.), Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, (M.D.H., S.N., A.R-H.), and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Manchester (M.R.R., A.R-H.), United Kingdom.

In drug development, considerable efforts are made to extrapolate from in vitro and preclinical findings to predict human drug disposition by using in vitro-in vivo extrapolation (IVIVE) approaches. Use of IVIVE strategies linked with physiologically based pharmacokinetic (PBPK) modeling is widespread, and regulatory agencies are accepting and occasionally requesting model analysis to support licensing submissions. Recently, there has been a drive to improve PBPK models by characterizing the absolute abundance of enzymes, transporters, and receptors within mammalian tissues and in vitro experimental systems using quantitative targeted absolute proteomics (QTAP). The absolute abundance of proteins relevant to processes governing drug disposition provided by QTAP will enable IVIVE-PBPK to incorporate terms for the abundance of enzymes and transporters in target populations. However, most studies that report absolute abundances of enzymes and transporter proteins do so in enriched membrane fractions so as to increase the abundance per sample, and thus the assay's sensitivity, rather than measuring the expected lower abundance in the more biologically meaningful whole cells or tissues. This communication discusses the balance between protein enrichment and potential loss during the preparation of membrane fractions from whole cells or tissues. Accounting for losses with recovery factors throughout the fractionation procedure provides a means to correct for procedural losses, thereby enabling the scaling of protein abundance from subcellular fractions to whole-cell or organ abundances. PBPK models based on corrected abundances will more closely resemble biological systems and facilitate development of more meaningful IVIVE scaling factors, producing more accurate quantitative predictions of drug disposition.
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http://dx.doi.org/10.1124/dmd.114.058446DOI Listing
October 2014

In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects.

Eur J Pharm Sci 2014 Jun 15;57:99-151. Epub 2014 Mar 15.

Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.
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http://dx.doi.org/10.1016/j.ejps.2014.02.010DOI Listing
June 2014

Alternative fusion protein strategies to express recalcitrant QconCAT proteins for quantitative proteomics of human drug metabolizing enzymes and transporters.

J Proteome Res 2013 Dec 31;12(12):5934-42. Epub 2013 Oct 31.

Manchester Pharmacy School, University of Manchester , Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom.

QconCAT is a tool for quantitative proteomics, consisting of an artificial protein, expressed from an artificial gene, made up of a concatenated string of proteotypic peptides selected from the proteins under study. Isotopically labeled QconCAT (usually containing (13)C6-arginine and (13)C6-lysine) provides a standard for each proteotypic peptide included in its sequence. In practice, some QconCAT proteins fail to express at sufficient levels for the purpose of quantitative analysis. Two complementary methods are presented to express recalcitrant QconCAT proteins intended to quantify human hepatic enzymes and transporters.
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http://dx.doi.org/10.1021/pr400279uDOI Listing
December 2013

Comparison of P-glycoprotein-mediated drug-digoxin interactions in Caco-2 with human and rodent intestine: relevance to in vivo prediction.

Eur J Pharm Sci 2005 Dec 8;26(5):386-93. Epub 2005 Sep 8.

University of Manchester, Gut Barrier Group, Clinical Sciences Building, Hope Hospital, Salford M6 8HD, UK.

Inhibition of P-glycoprotein (PGP) resulting from the co-administration of substrate drugs represents a potential source of drug-drug interactions. Although in vitro screens can readily identify such interactions, the accuracy with which they mimic interactions in tissues or their value in predicting interactions in vivo is unresolved. This was addressed for the model PGP substrate digoxin by comparing the modulation of its permeability across Caco-2 cells and ex vivo human and rodent intestine by drugs for which pharmacokinetic data on interactions with digoxin in man is available. All five compounds (talinolol, omeprazole, verapamil, quinidine, cyclosporin) dose-dependently increased absorptive (A-B) digoxin permeability with maximal increases of 2.2-4.5-fold across Caco-2. Quantitatively similar increases were observed in ex vivo human and mouse intestine and studies in mdr1a(-/-) intestine confirmed that these interactions are mediated solely by PGP. In vitro changes in digoxin permeability were qualitative indicators of the increase in digoxin C(max) for these compounds in man, although accounting for the luminal drug concentrations expected for a given oral dose was a critical consideration. Based on a limited dataset these data suggest that Caco-2 accurately mimics intestinal digoxin interactions and may be useful in predicting the threshold dose at which interactions become clinically significant. Further studies across a wider range of drugs are needed to determine the broader applicability of in vitro data for quantitative prediction of clinical drug interactions.
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http://dx.doi.org/10.1016/j.ejps.2005.07.013DOI Listing
December 2005