Colin Webber

Huntingdon Life Sciences, Huntingdon, England, United Kingdom

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Publications (8)7.31 Total impact

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    ABSTRACT: Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in dogs and also eliminated rapidly with a short half-life. Following single intravenous doses, dexloxiglumide was characterised as a drug having a high clearance (30.7 and 27.0 ml/min/kg in males and females respectively), a low volume of distribution (Vss, 0.34 and 0.27 L/kg in males and females respectively) and a moderate systemic availability (about 33%). It was extensively bound to plasma proteins (89%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the kidney, liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. 14C concentrations generally peaked at 0.25h and declined rapidly during 24h being present only in a few tissues (such as the kidney, liver and gastrointestinal tract) at 24h. Single intravenous or oral doses were mainly excreted in the faeces (77-89%), mostly during 24h. Urine contained up to 7.5% dose. Mean recoveries during 7 days ranged between 93-97%. Biliary excretion of 14C was prominent (64% dose during 24h) in the disposition of 14C which was probably also subjected to some limited enterohepatic circulation. Unchanged dexloxiglumide was the major component in plasma. Urine and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. about 55% dose in faeces). LC-MS/MS of urine and bile extracts showed that dexloxiglumide was metabolised mainly by O-demethylation and by conjugation with glucuronic acid.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2004; 29(1):15-23. DOI:10.1007/BF03190569 · 1.31 Impact Factor
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    ABSTRACT: The diffusion from the site of intramuscular injection of 900 kDa botulinum neurotoxin-hemagglutinin complex (BoNT/A-complex) and 150 kDa free-botulinum neurotoxin (free-BoNT/A) was compared. Radioiodinated compounds were injected into the gastrocnemius muscle of rats (70Units (U) 125I-BoNT/A-complex, 67 or 344 U free-125I-BoNT/A, or free-125I-iodide) and the eyelids of rabbits (24 U 125I-BoNT/A-complex or 108 U free-125I-BoNT/A), and measured in various tissues at different time points. There were no detectable systemic effects or generalized botulinum neurotoxin toxicity in either rats or rabbits, indicating that most of the toxin, whether as 125I-BoNT/A-complex or free-125I-BoNT/A, remained at the injection site. In rats, 125I-BoNT/A-complex and free-125I-BoNT/A diffused in a pattern that was grossly similar. Almost no radioactivity was recovered from the brain. Radioactivity recovered from distant tissues (thyroid, skin, and contralateral muscle) was primarily attributable to either low molecular weight 125I-containing peptides or 125I-iodide. After injection into rabbit eyelids, neither 125I-BoNT/A-complex nor free-125I-BoNT/A spread to distant structures, including the eye. The results indicate that most of the neurotoxin does not diffuse from the injection site, whether in free or complexed form, and this may reduce the potential for systemic effects.
    Toxicon 11/2003; 42(5):461-9. DOI:10.1016/S0041-0101(03)00196-X · 2.58 Impact Factor
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    ABSTRACT: Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.
    European Journal of Drug Metabolism and Pharmacokinetics 09/2003; 28(3):201-12. DOI:10.1007/BF03190486 · 1.31 Impact Factor
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    ABSTRACT: 1. Mean concentrations of total (14)C and of dexloxiglumide at the end of single 20-min infusion doses of (14)C-dexloxiglumide (200 mg) to four healthy male subjects were 18.5 microg eq x ml(-1) and 19.5 microg ml(-1) respectively. The mean plasma clearance (0.22 l h(-1) x kg(-1)) and mean volume of distribution (V(ss) = 0.18 l kg(-1)) were low. 2. Single oral doses of a solid formulation of (14)C-dexloxiglumide (200 mg) to the same subjects appeared to be rapidly and well absorbed. Mean peak plasma concentrations (C(max)) of total (14)C (2.8 microg eq x ml(-1)) and of dexloxiglumide (2.2 microg x ml(-1)) occurred at about 1.5 h. Systemic availabilities of the oral dose based on total (14)C and dexloxiglumide were 70 and 48%, respectively. Thus, a proportion of an oral dose was subjected to presystemic elimination and the absorbed dose mainly eliminated by metabolism. Binding of dexloxiglumide to plasma proteins was extensive (96.6-99.2%). 3. Total (14)C was excreted mainly in the faeces. Mass balance of (14)C excretion was almost complete within 7 days when a mean of > 93% of the dose had been recovered. After the intravenous (i.v.) dose, mean totals of 23.7 and 69.8% of the dose were excreted in urine and faeces, respectively, during 7 days, and 19.5 and 73.7% of the dose, respectively, after the oral dose. The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites. 4. LC-MS/MS of urine extracts showed that dexloxiglumide was metabolized by oxidation and conjugation. The former included at least two metabolites formed by monohydroxylation in the N-(3-methoxypropyl) pentyl side chain, and O-demethylation of this side chain followed by subsequent oxidation of the resultant alcohol to the dicarboxylic acid. At least one glucuronide was also present in urine. The main components in faeces appeared to be dexloxiglumide and a dicarboxylic metabolite formed by O-demethylation followed by oxidation of the N-(3-methoxypropyl) side chain. Both compounds were identified as their corresponding methyl esters formed because acid and methanol were used in the extraction procedure. Dexloxiglumide and the dicarboxylic acid were presumably excreted in bile as the glucuronic acid conjugates.
    Xenobiotica 07/2003; 33(6):625-41. DOI:10.1080/0049825031000089137 · 2.10 Impact Factor
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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.
    10th European Regional International society for the study of xenobiotics Meeting;
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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.
    8th International International society for the study of xenobiotics Meeting;
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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%).
    11th European Regional International society for the study of xenobiotics Meeting;
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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.
    9th International International society for the study of xenobiotics Meeting;