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-hydroxyphenyltrimethylammonium (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.
I 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 gmol/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 imol/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.
AB9 2ZD and tDepartment of Clinical Pharmacology, The Royal Infirmary, Edinburgh EH3 9YW1 The pharmacokinetics of y-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-'. 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 kg1 and elimination rate constant of 2.99 + 0.27h1. 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 + 0.181 kg -. 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.
The concentration of oxytetracycline in plasma was studied by microbiological assay after oral administration of four different preparations of oxytetracycline dihydrate tablets.
There were statistically significant differences in biological availability between the four preparations, as assessed by the peak plasma level, the area under the plasma concentration‐time curve, or the cumulative fraction of the dose excreted in urine at 405 minutes. In contrast, differences between the subjects were not statistically significant.
The differences in biological availability were not predictably related to the in vitro dissolution of the tablets.
The distribution kinetics of inulin and urea were studied in the male rat to test the validity of a proposed compartmental model. The plasma curves could be adequately described by a biexponential function. For inulin, analysis of the results gave valid parameters in terms of an open two compartment model. These parameters did not necessarily predict the amount eliminated from the central compartment but did so under constant clearance conditions after allowance for a time lag between filtration and appearance of the drug in the collecting vessel. A triexponential fit interpreted in terms of a three compartmental model described the urea data.
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