D. S. Hewick
University of Dundee
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Journal of Pharmacy and Pharmacology | 1973
D. S. Hewick; John Mcewen
S‐(‐)‐Warfarin was found to be a more potent anticoagulant than R‐(+)‐warfarin in man. However, S‐warfarin was cleared more rapidly from the plasma; respective mean plasma half‐lives (from four subjects) for R and S‐warfarin were 45ṁ4 and 33ṁ0h. Unlike the assay of Lewis, Ilnicki & Carlstrom (1970), the assay of Corn & Berberich (1967) for measuring plasma warfarin gave spuriously long half‐life values, particularly with R‐warfarin. The apparent volumes of distribution of the enantiomers were not significantly different. A major plasma metabolite detected was warfarin alcohol1, which was seen in much greater quantities after giving R‐warfarin than after S‐warfarin. The corresponding diastereoisomer, warfarin alcohol2, was seen in trace amounts after S‐warfarin only.
Journal of Pharmacy and Pharmacology | 1992
M. P. Timsina; D. S. Hewick
Abstract— A 2 mg kg−1 intravenous bolus dose of digoxin‐specific Fab fragments produced a 28% reduction in creatinine clearance in rabbits after 24 h. Urine output was reduced, while plasma and urinary creatinine concentrations were unaffected and increased, respectively. By 5 days the creatinine clearance had returned to normal. The fractional excretion of Na+ was nearly halved, indicating that the tubular reabsorption of Na+ increased to compensate for the reduced glomerular filtration rate, suggesting that tubular (as opposed to glomerular) function was not impaired.
Journal of Pharmacy and Pharmacology | 1972
D. S. Hewick
Warfarin as used rodenticidally and clinically is a racemic mixture of two enantiomers. In normal male rats (-)-warfarin is about six times more potent as an anticoagulant than (+)-warfarin (Eble, West & Link, 1966; Breckenridge & Orme, 1972). Also in normal male rats (-)-warfarin is eliminated from the plasma at about half the rate of (+)-warfarin (Breckenridge & Orme, 1972). I have examined the warfarin enantiomers in both normal and warfarin-resistant rats of either sex. Rats (average weight 220 g) homozygous for warfarin resistance (SH strain) and normal warfarin-susceptible Sprague-Dawley rats were used. Phenobarbitonepretreatment comprised five consecutive daily injections of phenobarbitone sodium (75 mg/kg); the last injection was made approximately 24 h before warfarin injection. Blood samples (obtained by aortic puncture) were citrated and then centrifuged to obtain the plasma. Plasma prothrombin times were determined by the method of Quick (1957). Plasma warfarin was determined by the method of Corn & Berberich (1967). Table 1 shows that in each sex of both resistant and non-resistant rats (+)-warfarin was eliminated from the plasma two to three times faster than (-)-warfarin. The plasma half-lives of the respective enantiomers were almost identical in male resistant and male non-resistant rats. The half-lives of the respective enantiomers in female resistant rats were about two-thirds of those in female non-resistant rats. The apparent volumes of distribution of the enantiomers were similar in both rat strains (results not shown). Also similar in both strains was the lower rate of elimination of the enantiomers by female rats. However, Table 1 shows significant differences between the strains in the susceptibility to the anticoagulant action of warfarin. At 31 h after warfarin administration the prothrombin times of the resistant rats were hardly affected while those of the non-resistant rats were markedly prolonged. The prothrombin times show in normal male and female rats that (-)-warfarin was more potent than (+)-warfarin. In a
Journal of Pharmacy and Pharmacology | 1992
M. P. Timsina; D. S. Hewick
Abstract— Administering digoxin‐specific antibody fragments (DSFab, 1·9 mg kg−1, i.v.) to rabbits 1 h after digoxin (15 μg kg−1 or 12·5 μCi kg−1, i.v.) produced a redistribution of digoxin associated with a 5‐fold elevation in total plasma concentration and 36–86% reductions in elimination half‐life, apparent volume of distribution at steady‐state and total body clearance (CLT). Renal clearance (CLR) was also reduced (54%), but urinary digoxin excretion was increased by one‐third (35% vs 25%). This apparent anomaly is due to the large rise in total plasma digoxin concentration with a consequent increase in the area under the plasma concentration curve (AUC). The AUC, which is the denominator term in calculating CLR (and CLT), was increased to a greater extent than urinary digoxin excretion (numerator term in calculating CLR) so that an overall reduction in CLR occurred. The initial presence of digoxin appeared to alter the distribution of DSFab, since their plasma concentrations were markedly higher when the antibody was given after the hapten. The digoxin also reduced (from 3 to 1%) the amount of detectable DSFab in the urine.
Biochemical Pharmacology | 1984
Nina M. Griffiths; D. S. Hewick; I. H. Stevenson
After intravenous dosing, digoxin was rapidly distributed to tissues, with a distribution half-life of 3.0 min. The highest digoxin concentrations at 1 hr post dosing were found in lymph nodes, adrenals, gallbladder (including contents), liver and kidney respectively. Digoxin concentrations in the heart, spleen, brain, lung, skeletal muscle and fat were similar to, or lower than, those in the plasma. The apparent volume of distribution (AVd) was 1 l/kg, and the plasma elimination half-life and clearance (Cl) 2.8 hr and 0.25 l/kg per hr respectively. When digoxin was given one day after passive immunization with digoxin-specific immunoglobulin G (IgG) or Fab fragments the respective plasma digoxin concentrations were elevated some 26- and 5-fold respectively compared with control values. Consequently there were reductions in AVd (93 and 32%) and Cl (94 and 50%). The effect of IgG treatment on clearance was still apparent when the hapten was given up to 14 days after immunization, while the weaker effect of Fab-treatment was less persistent. Although tissue digoxin concentrations were slightly lower in the immunised mice, it was only in the lymph nodes at 10 and 14 days after IgG treatment that the reduction in hapten concentration was statistically significant.
Journal of Pharmacy and Pharmacology | 1976
D. S. Hewick; A. M M Shepherd
ADAMS, S. S., CLIFFE, E. E., LESSEL, B. & NICHOLSON, J. S. (1967). J.pharrn. Sci., 56,1686. ADAMS, S . S., MCCULLOUGH, K. F. & NICHOLSON, J. S. (1969). Archs int. Pharmacodyn. Thkr., 178, 115-129. BROOKS, C. J. W. & GILBERT, M. T. (1974). J. Chromatog., 99, 541-551. FLOWER, R. J., GRYGLEWSKI, R. HERBACZYNSKA-CEDRO, K. &VANE, J. R. (1972). Nature New Biol., 238,104-106. GREIG, M. E. & GRIFFIN, R. L. (1975). J. medl Chem., 18, 112-116. HAM, E. A., CIRILLO, V. J., ZANETTI, M., SHEN, T. Y. & KUEHL, F. A. (1972). Proc. ALZA Conf. 1971 : Prostaglandins in cellular biology and the inflammatoryprocesses. Editor: Ramwell, P. W., pp. 345-352. New York: Plenum. MILLS, R. F. N., ADAMS, S. S., CLIFFE, E. E., DICKINSON, W. & NICHOLSON, J. S. (1973). Xenobiotica, 3,589-598. SHEN, T. Y. (1967). Ann. Rep. Med. Chem., p. 215. TAKEGUCHI, C. & SIH, C. J. (1972). Prostaglandins, 2, 169-184. TOMLINSON, R. V., RINGOLD, H. J., QURESHI, M. C. & FORCHIELLI, E. (1972). Biochem. Biophys. Res. Comm.,46,
Biochemical Pharmacology | 1987
Pauline C. Johnston; I. H. Stevenson; D. S. Hewick
Pentobarbitone-anaesthetized bile duct-cannulated female rats were injected intravenously with an equimolar dose of digoxin-specific sheep antibody fragments (DS-Fab) at 2 or 60 min after a dose of [3H]digoxin. The plasma drug levels were promptly elevated by 7-fold or 12-30-fold when the DS-Fab were given at 2 or 60 min respectively. When tissue drug concentrations were measured 2 min after a dose of DS-Fab (given 60 min after digoxin) which caused a 30-fold increase in plasma concentration, reductions could be detected if corrections were made for the presence in the tissues of high plasma concentrations of DS-Fab-bound drug. For instance, reductions in the heart, liver and small intestine were 63, 58 and 48% respectively. However, by 120 min after digoxin injection the only detectable effects on tissue drug concentration were in the kidney, where concentrations had increased 14-fold or 7-fold when the DS-Fab were given at 2 or 60 min respectively. Over the 120 min period the urinary excretion of digoxin-derived radioactivity was enhanced, and in the case where DS-Fab were given at 2 min, a 3-fold increase in urinary excretion was seen, which resulted in a net increase in the overall drug elimination. This greater urinary elimination was accompanied by a marked increase in the amount of bound drug in the urine (control and experimental values were 4 and 36% respectively). The cumulative biliary excretion of radioactivity seemed to be slightly reduced by DS-Fab administration at 2 or 60 min, although this was not statistically significant. A lack of significant drug-specific binding in the bile suggested that the liver is not involved in the elimination of hapten-DS-Fab complexes. There was little effect on the intestinal secretion of the drug.
Journal of Pharmacy and Pharmacology | 1978
D. S. Hewick; V. Shaw
Both in patients and healthy volunteers old age is associated with an increased sensitivity to the hypnotic nitrazepam (Evans & Jarvis, 1972; Castleden, George & others, 1977). Plasma concentration data indicate that this is partly due to altered pharmacokinetics in aged patients (lisalo, Kangas & Ruikka, 1977) but not in healthy aged subjects (Castleden & others, 1977). To examine the problem of age-related increased nitrazepam sensitivity further, we decided to measure the concentrations of radioactivity in the brain and other tissues of young and old rats at various times after a single dose of [14C]nitrazepam. An additional purpose of this work was to supplement the limited information available on the tissue distribution of nitrazepam, concentrations only having been previously determined in blood, brain and liver (Tanayama, Momose & Kanai, 1974; Yanagi, Haga & others, 1975). “Young” (100 days old) and “old” (540 days old) male Wistar rats were injected with 5[14C]nitrazepam 40 mg kg-’ (4.2 pCi kg-I), intraperitoneally to avoid any possible age related variation in drug absorption from the gastrointestinal tract, the drug being dissolved in dimethylsulphoxide (40 mg ml-l) which was chosen because it appears to have no effect on the onset or duration of action of centrally acting drugs (see e.g. Dixon, Adamson & others, 1965). The rats were killed at 2, 3 .3 , 4.7 and 6 h after injection and blood and tissue (brain, spleen, kidney, liver, heart, lung and small intestine) samples were taken for measurement of radioactivity by liquid scintillation spectrometry. For this aqueous tissue homogenates (25 % w/v) were prepared and 0.25-0.5 ml samples were digested (heated for 1 h at 60” with 1 ml Soluene, Packard Instrument Co., Inc. Illinois) and decolourized (0.2 ml isopropanol followed by 0.2 ml 30-35 % hydrogen peroxide) in counting vials before the addition of 10 ml of a toluene-based scintillator (NE 260, Nuclear Enterprises Ltd., Edinburgh) to each. Erythrocytes were diluted with an equal volume of water and 0.2 ml aliquots treated similarly to the tissue samples except that 0.5 ml Protosol (33% v/v in ethanol) and 15 ml Biofuor (New England Nuclear, Boston, Mass.) were used as the solubilizer and scintillator respectively and 0.5 ml of 0.5 M hydrochloric acid solution was added to each vial before counting. In a few young rats [14C]nitrazepam of a higher specific activity (40 mg kg-l, 20 pCi kg-I) was injected to facilitate drug/metabolite analysis. Where the drug of higher specific activity had been used the rats were killed after 3 h and homogenates of brain and liver were made alkaline and extracted with butan-1-01 (95 % of radio-
Journal of Pharmacy and Pharmacology | 1990
M. P. Timsina; D. S. Hewick
Abstract— The plasma disposition of sheep polyclonal digoxin‐specific Fab (fragment antigen‐binding) fragments has been studied in rabbits after their intravenous injection (1 mg kg−1) using enzyme‐linked immunosorbent assays exploiting both the species‐specificity (ELISAi) and the digoxin‐specificity (ELISA2) of digoxin‐specific Fab fragments. The log concentration versus time profiles were best described by a biexponential plasma disposition when either assay was used. Although the plasma concentrations determined by ELISA, and ELISA2 at each sampling time were not significantly different, there was a tendency for certain ELISA2 values to be higher. This resulted in the ELISA2‐derived data giving a significantly longer distribution half‐life (t 1/2α), but similar values for elimination half‐life (t 1/2β), apparent volume of distribution at steady state (Vdss), and clearance. Using ELISA2, which was generally the more sensitive assay, to compare the plasma disposition of the sheep polyclonal digoxin‐specific Fab fragments with rat monoclonal digoxin‐specific Fab fragments, it was shown that the rat product had a shorter t 1/2α (11 vs 22 min), a t 1/2β which was not significantly different (253 vs 168 min), but a faster clearance (1.2 vs 0.7 mL kg−1 min−1), associated with a much larger Vdss (321 vs 108 mL kg−1). The extracellular fluid volume, using thiocyanate as a marker, was about 216 mL kg−1 for the nine rabbits used. This suggests that the rat preparation penetrates more extensively into the extracellular space and may indicate that some degree of extracellular binding or cell penetration is occurring.
Journal of Pharmacy and Pharmacology | 1991
M. P. Timsina; D. S. Hewick
Abstract— The plasma kinetics of total and free digoxin, and digoxin‐specific antibody fragments (DSFab) in rabbits which had been given [3H]digoxin one hour before DSFab has been studied over a 5 day period. Injection of DSFab caused a 4‐ to 5‐fold rise in total digoxin and reduced elimination half‐life (t½β), apparent volume of distribution at steady‐state (Vdss) and systemic clearance (CL) by 40, 90 and 75% respectively. Early in the experimental period, DSFab reduced free digoxin concentration (measured by ultrafiltration) from 4·1 ng mL−1 to a minimum of 1·3 ng mL−1 at 15 min. However, the concentration had rebound to 2·5 ng mL−1 by 60 min. Subsequently, free digoxin fell to 0·63 ng mL−1 and remained relatively constant over a 7 to 90 h period. The distribution half‐life, t½β, Vdss and CL for DSFab (concentrations measured by enzyme‐linked immunosorbent assay) were 0·3 h, 3·2 h, 185 mL kg−1 and 57 mL kg−1 h−1, respectively. A considerable molar excess (about 5) of DSFab in the plasma was necessary to maintain minimum free digoxin concentrations. When the DSFab:digoxin molar ratio was less than 4 during the initial treatment period, free (toxicologically active) concentrations increased. With the elevation in total digoxin, however, an opposite situation appeared to apply. By 24 h the relatively short DSFab t½β meant that the plasma DSFab concentration was < 0·05 μg mL−1 giving a DSFab:digoxin molar ratio of below 006, yet the antibody‐induced rise in total digoxin concentration was still detectable at 100 h.