Colin Webber

Huntingdon Life Sciences, Huntingdon, England, United Kingdom

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Publications (4)16.07 Total impact

  • Richard Harrison · Colin Webber · Rosie Yu · Richard Geary
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    ABSTRACT: ISIS 388626 is a 2'‑O‑methoxyethyl‑modified (2'MOE) phosphorothioate oligonucleotide with 12 nucleotides in length (12-mer) currently under development for use in the treatment of Type 2 diabetes mellitus. It is an antisense drug designed to inhibit the expression of human sodium-dependent glucose cotransporter 2 (SGLT2), a key component in controlling glucose re-absorption in the kidney. The study described was conducted to obtain information on the pharmacokinetics, distribution, metabolism, excretion and mass balance of [35S]‑ISIS 388626 in the rat. Male and female Sprague-Dawley CD rats each received a single subcutaneous administration of [35S]‑ISIS 388626 as a solution in phosphate buffered saline (PBS) at target dose levels of 3 or 10 mg/kg. In addition, one male rat received a single subcutaneous administration of PBS only. Levels of radioactivity were determined in plasma, tissues and excreta by liquid scintillation analysis. The distribution of radioactivity was also investigated using quantitative whole body radioluminography and in kidney by microautoradiography. Radioactive components present in urine, faeces and kidney were separated and quantified using HPLC coupled with radioactivity detection or mass spectrometry. The results demonstrated: 1) rapid absorption, with maximum concentrations of radioactivity in blood and plasma attained 1 h post-dose, followed by a multi-phasic, protracted decline, consistent with slow elimination from tissues; 2) [35S]‑ISIS 388626 related radioactivity was cleared rapidly from blood, predominantly due to distribution into tissues, with the kidneys being the major tissue of distribution (approximately 45% of the administered dose at 24 h post-dose), with low levels also observed in the axillary and mesenteric lymph nodes, skin, liver and thyroid (more than 20 fold lower than in the kidneys); 3) the presence of radioactivity in the tubular epithelium, with a relatively uniform distribution throughout the kidney cortex and little radioactivity scattered in the kidney medulla; 4) slow clearance from tissues, with an elimination half‑life typically between one to three weeks; 5) the majority of the administered radioactivity (approximately 91.4% of dose) was eliminated by 28 d post‑dose, with approximately two thirds in urine and the remainder in faeces; 6) slow metabolism in tissues, principally via nuclease mediated cleavage, which was followed by elimination in urine and faeces.
    No preview · Conference Paper · Aug 2010
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    ABSTRACT: The pharmacokinetics, tissue distribution, metabolism and excretion of Zabofloxacin (1-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid hydrochloride; also known as DW-224a and PB-101, a new broad-spectrum fluoroquinolone-type antibiotic with enhanced in vitro activity against Streptococcus pneumoniae, including strains resistant to other antibiotics, was investigated in non-fasted male rats after oral administration of [14C]Zabofloxacin hydrochloride (100 mg salt/kg) as a solution in purified water. In intact non-fasted SD rats, the total recovery of radiolabelled dose after seven days was 93.2% and most of the dose (90.2%) was eliminated in faeces, with about 2.9% dose excreted in urine. In bile duct-cannulated fasted SD rats, the highest proportion of the dose was also recovered in the faeces (72.9%), with 7.0% and 5.8% of the dose excreted in urine and bile, respectively. The total circulating drug-related material (represented by 14C-radioactivity) increased to a Cmax of .91 g equivalents free base/mL after 1 h. Tissue concentrations of drug-related material were generally maximal between 0.5 1 h post-dose, with the highest concentrations seen in the small intestine, liver and stomach wall. Tissue concentrations declined and at 24 hours all tissues were below the level of quantitation except for skin, wall of the large intestine and rectum. In the non-fasted pigmented (Lister-Hooded) rats, tissue concentrations were highest in the eyes, pigmented skin and liver; after 24 hours radioactivity in the eyes persisted up to and including 112 days post-dose, indicating, binding of drug-related material to ocular melanin. Oral absorption of [14C]Zabofloxacin hydrochloride was poor in non-fasted rats (< 15%) compared to fasted rats (30%).
    No preview · Conference Paper · May 2009
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    ABSTRACT: Huntingdon Life Sciences is one of the leading contract facilities for respiratory safety assessment, a service for which there is currently increasing demand. This presentation focuses specifically on recently conducted inhaled dose ADME studies and seeks to address some common questions about such work. The review includes both rodent and non-rodent studies, in which aerosols of radiolabelled test compounds have been generated from dry powders, solutions or MDIs. Reproducing the aerosol characteristics of non-radiolabelled test compounds for the much smaller amounts of radiolabelled compound usually available is a key challenge when using dry powder aerosols. In our laboratories, sub-gram amounts of radiolabelled dry powders have been micronised by ball-milling (ambient or cryogenic) to routinely produce material with MMAD < 2 microns and inhalable fraction > 90%, broadly consistent with larger-scale non-radiolabelled batches. Inter-animal variability in inhalation dosing is also a major consideration in ADME study design and data interpretation. Achieved radioactive dose levels shed light on variability that is likely to be encountered during toxicology studies where achieved dose levels cannot be directly measured. Dose quantification for rodents in snout-only exposure chambers is achieved by radioactivity analysis of a small number of animals killed immediately after exposure, the mean total amount measured being taken to represent the dose received by each of the other animals on the chamber. This includes radioactivity deposited on the body surface, mainly around the snout, which typically represents about 25% of the total and will subsequently be ingested during preening. Our data confirm some inter-animal variation in both the relative proportions of deposited and inhaled radioactivity and the overall dose level achieved during a single exposure (CV typically >20%). Consequently, total apparent recoveries of radioactivity during rodent excretion balance studies, expressed as % estimated dose, are likely to show similar inter-animal variation. For non-rodents, dose quantification is achieved by rigorous analysis of the dose utensils used for each animal, subtracting residual radioactivity from the amount dispensed during exposure. This approach results in a more accurate individual dose assessment such that excretion recoveries usually show little variation. This poster includes specimen data from rats and dogs and reviews ways in which these studies may be designed and interpreted to ensure that conclusions are scientifically robust.
    No preview · Conference Paper · Jan 2008
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    ABSTRACT: The herbicide paraquat, both alone and in combination with the fungicide maneb, has been suggested as a risk factor in the development of Parkinson's disease in humans. Huntingdon Life Sciences is currently conducting a lifetime study in mice to investigate this on behalf of Exponent, Inc. Prior to the commencement of this study, a series of experiments in juvenile and adult C57Bl/6 mice (the standard animal model for Parkinson's disease) were conducted to establish human-relevant dose levels and assist in other aspects of the study design. The primary objective of these preliminary experiments was to populate a physiologically based pharmacokinetic (PBPK) model for [14C]paraquat distribution in the mouse. Dose routes used were dermal, oral and intranasal (a surrogate for inhalation), as those typically responsible for human exposure, and intraperitoneal to bridge with previous data. This in turn allowed construction of a human PBPK model, based upon the mouse data and published parameters relevant to humans. The mouse PBPK model described adult blood paraquat concentrations well for all routes and brain paraquat concentrations well for dermal, intraperitoneal and oral administration in adults, but under-predicted those following intranasal doses. This, together with the unexpected finding that radioactivity concentrations differed between the two hemispheres of intranasally dosed mice (up to about 8-fold), indicate that for this route, transfer to the brain is not solely dependent on systemic circulation. A subsequent experiment, dosing into a single nostril, demonstrated even greater variation (up to about 50-fold) and a link between the side dosed and the hemisphere of greatest concentration. In addition, a number of other investigations into the administration of doses to juvenile mice, including aspects of animal husbandry, were carried out. These established that it was possible to administer intraperitoneal doses of paraquat to juvenile mice on post-natal day 5 (PND5) without clinical signs, morbidity or rejection by the dam. Furthermore, the juvenile mice tolerated repeated daily intraperitoneal administration of paraquat between PND5 and PND19 without any obvious impact on development or subsequent weaning. It was also shown that after administration of [14C]paraquat to a single pup within a litter, radioactivity was not detectable in other pups 24 hours later, demonstrating negligible transfer of the non-metabolised and water soluble paraquat via the dam. Sponsored by the Department for Environment, Food and Rural Affairs (DEFRA), Pesticides Safety Directorate, United Kingdom government.
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