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Biomedical subjects

H E Barber

Publications and source records attributed to H E Barber.

At least 19 recordsLinked to original sources
PubMed1991

Disposition of gamma-glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg-1 and 100 micrograms kg-1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/- 1.50 ml min-1 kg-1 and 4.92 ml min-1 kg-1 at the higher and lower doses, respectively. Corresponding half-lives were 29.2 +/- 3.7 min and 32.5 +/- 5.6 min, and volumes of distribution were 0.183 +/- 0.052 l kg-1 and 0.235 +/- 0.07/ l kg-1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro-drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.

Adult↗
PubMed1990

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg-1. 2. Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 +/- 9.6 ml min-1 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. The mean residence time and half-life were 20.9 +/- 1.4 and 14.4 +/- 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 +/- 0.18 l kg-1. 3. No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4. In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5. These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.

Acute Kidney Injury↗
PubMed1986

The kinetics of 4-nitrophenol conjugation by perfused livers and hepatic microsomes from streptozocin-induced diabetic rats.

The formation of both glucuronide and sulphate conjugates of 4-nitrophenol is deficient in perfused livers from male diabetic rats. Experiments with 'native' hepatic microsomes demonstrated that the defect in glucuronidation is due to a decrease in the maximal velocity of the reaction. There is no alteration in the affinity of the glucuronyltransferase for 4-nitrophenol. Non-linear regression analysis of the 4-nitrophenol liver perfusate concentrations showed that the elimination follows saturable Michaelis-Menten kinetics. Clearance values in 'native' microsomal preparations and in perfused livers were calculated and found to be similar in both systems. This provides evidence that glucuronyltransferase is 'native' in the intact liver.

Animals↗
PubMed1979

The relationship between the pharmacokinetics, cholinesterase inhibition and facilitation of twitch tension of the quaternary ammonium anticholinesterase drugs, neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium.

1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethyl-ammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred. Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme.

Acetylcholinesterase↗
PubMed1976

Plasma concentration of edrophonium in man.

The plasma concentration of edrophonium was measured in man after intravenous administration. In 5 patients, the clearance of edrophonium from the circulation during the 1-hr period of sampling was invariably resolved into 2 exponential components. An initial rapid phase of elimination from plasma (T/2 = 0.54 TO 1.92 Min) was followed by a much slower decline (T/2 = 24.23 to 45.00 Min), corresponding to the fall in concentration between 10 and 60 min. In parallel experiments in the rat, the clearance of 14C-edrophonium was resolved into 3 exponential components, although the final component could not be reliably defined until 1 to 3 hr after intravenous injection. It is suggested that the rapid fall in the plasma concentration of edrophonium in both species is not dependent on metabolism or excretion, but is due to the rapid uptake of the drug by the liver and kidneys.

Acetylcholinesterase↗
PubMed1976

The effect of edrophonium on erythrocyte acetylcholinesterase and neuromuscular function in the rat.

1. The relation between the concentration of edrophonium in plasma, inhibition of red cell acetylcholinesterase, and neuromuscular transmission was studied in the rat. 2. In both in vivo and in vitro conditions, red cell acetylcholinesterase activity was predictably related to the concentration of the quaternary amine. 3. After low doses of edrophonium (1.0 mumol/kg) there was a significant correlation between the monophasic potentiation of twitch tension and the plasma concentration of the drug. In contrast, with higher doses of edrophonium (4.0 or 10.0 mumol/kg) a biphasic potentiation of twitch tension was observed; this was only correlated with the plasma concentration of the drug during the secondary decline in neuromuscular facilitation. Subsequent recovery of normal neuromuscular transmission invariably occurred at a constant plasma concentration of edrophonium.

Acetylcholinesterase↗
PubMed1975

The effect of hydrocortisone phosphate, methylprednisolone and phenytoin on pancreatic insulin release and hepatic glutathione-insulin transhydrogenase activity in the rat.

Following i.v. injection of glucose to rats, blood was collected from the carotid artery and the portal vein, and insulin was determined by radioimmunoassay. Pancreatic insulin release and hepatic insulin extraction were increased following the administration of glucocorticoid drugs and reduced following phenytoin. Hepatic glutathione-insulin transhydrogenase activity (GITA) was measured in each animal and found to be increased after glucocorticoid therapy but unaffected by phenytoin. In alloxan-diabetic rats, GITA was significantly increased following treatment with both methylprednisolone and phenytoin compared with control alloxan-diabetic rats. This is suggestive evidence that both these drugs can initiate an increase in GITA. It is concluded that the markedly raised GITA in steroid-treated non-diabetic rats is the combined result of a drug-induced effect plus the major inducing effect of an increased hepatic uptake of insulin on insulin degradation, whereas the main effect of phenytoin is a reduction of pancreatic insulin release.

Animals↗
PubMed1975

The effect of codeine phosphate on the absorption of ethyl alcohol.

The effect of syrup, B.P. and codeine phosphate syrup, B.P.C. on blood alcohol levels was determined in six normal subjects. 2 Treatment with syrup alone had little or no influence on the concentration of ethanol in blood. 3 In contrast, pretreatment with codeine phosphate syrup significantly reduced alcohol absorption, as assessed by the maximum blood levels achieved or the area subtended by the blood concentration-time curve. It is suggested that the diminished absorption of ethanol is related to the pharmacological action of codeine on the stomach. 4 It was considered that the concentration of ethanol in linctuses or syrups containing codeine was unlikely to have any significant effect on the central nervous system.

Codeine↗
PubMed1975

Bioavailability and dissolution of different formulations of oxytetracycline preparations.

1 The concentration of oxytetracycline in plasma was studied by microbiological assay after oral administration of five different preparations of the antibiotic. None of these preparations had been studied previously. 2 There was a statistically significant correlation between the time required for 50% dissolution at pH 2 and biological availability, as assessed by the peak plasma level or the area under the plasma concentration-time curve. 3 The mean bioavailability of oxytetracycline was greatest with preparations of the hydrochloride, and with film-coated tablets of the dihydrate. In contrast, sugar-coated tablets of oxytetracycline dihydrate were associated with poorer dissolution characteristics and reduced biological availability.

Biological Availability↗
PubMed1975

The pharmacokinetics of pyridostigmine and 3-hydroxy-N-methylpyridinium in the rat: dose-dependent effects after portal vein administration.

1 The elimination kinectis of [14C]-pyridostigmine iodine and [14-C-methyl]-3-hydroxypyridinium bromide (3-OH NMP) have been studied in the rat. 2 For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver. 3 When doses of pyridostigmine 1.25 mumol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose-dependent process is involved in the urinary excretion of 3-OH NMP. 4 This conclusion was supported by studies involving the portal and systemic venous injection of 3-OH NMP at different dose levels. After 4 h, approximately85% of the lowest dose was eliminated unchanged in ug this period. The proportion of the dose eliminated in urine was not related to the route of administration. 5 After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug.

Animals↗
PubMed1974

The pharmacokinetics of neostigmine and 3-hydroxyphenyltrimethyl- ammonium in the rat: dose-dependent effects after portal vein administration.

1 The elimination kinetics of [(14)C]-neostigmine iodide and [(14)C]-3-hydroxyphenyltrimethyl-ammonium iodide (3-OH PTMA) have been studied in the rat.2 The presence of a renal secretory pathway for neostigmine and 3-OH PTMA has been confirmed.3 For neostigmine and 3-OH PTMA, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that both compounds are subject to extensive metabolism during the first passage through the liver.4 Neostigmine was eliminated by dose-independent kinetics after jugular vein administration but dose-dependent after portal vein administration. In the latter case the fraction eliminated as neostigmine increased with increasing dose. This increase was not accompanied by any change in the fraction of the metabolites eliminated.5 After portal vein administration of 3-OH PTMA, the fraction of the dose eliminated as 3-OH PTMA also increased with increasing dose. This change was accompanied by a decrease in the fraction of the metabolites eliminated which were excreted at a constant rate.

Animals↗