Pharmacokinetics of metoclopramide.
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Biomedical subjects
Publications and source records attributed to D S Davies.
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A highly sensitive and specific assay is described for the bronchodilator drug terbutaline in human plasma and urine, based on single ion monitoring gas chromatography mass spectrometry and employing a homologue of the drug as internal standard. Recovery of terbutaline and internal standard into ethyl acetate is effected at pH 9.8, while back-extraction into dilute acid serves to purify the initial extract. Following preparation of O-TMS, N-TFA derivatives, the drug and its homologue are detected by selected ion monitoring of their common base ion at m/e 355. The limit of detection of terbutaline by this procedure is 0.3 ng ml-1 from a 4 ml sample of plasma.
1-Norepinephrine was infused continuously for 10 hr into 5 normotensive, male laboratory subjects (mean age, 32.4 +/- 1.9 yr) at a mean rate of 0.06 microgram/kg/min. Mean plasma norepinephrine (NE) rose from the preinfusion level of 0.19 +/- 0.02 microgram/l to a steady state level of 1.22 +/- 0.29 microgram/l. The mean increase in blood pressure was 21.8 +/- 0.9 mm Hg systolic and 14.1 +/- 1.0 mm Hg diastolic. The mean depression in heart rate was 12.7 +/- 1.7 beats/min. The clearance of norepinephrine ranged from 27.9 to 100.0 ml/kg/min (mean. 58.0 +/- 13.8) and was little influenced by acute hemodynamic changes. The volume of distribution ranged widely (0.09 to 0.40 l/kg), the mean value being 13.51 1. The mean norepinephrine half-life was brief, ranging from 1.45 to 2.9 min (mean, 2.09 +/- 0.34 min). There was no evidence of a slowly accumulating high-capacity low-affinity pool of norepinephrine. These results support the use of plasma norepinephrine as an index of sympathetic activity within an individual but not its validity in interindividual comparisons.
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1 Twenty-four Asian vegetarians had significantly lower 25-hydroxyvitamin D (25-OHD) levels and longer antipyrine half-lives than twenty white non-vegetarians (P less than 0.001). 2 Treatment with oral antipyrine over 4 or 5 weeks in seven vegetarian Asians and five racially different non-vegetarians increased drug oxidation significantly in both groups as measured by a fall in antipyrine half-lives and a rise in serum gamma-glutamyltranspeptidase levels and urinary 6 beta-hydroxycortisol/17-hydroxycorticosteroid ratios. 3 Antipyrine treatment produced a fall in circulating 25-hydroxyvitamin D of around 60% in all subjects in whom pretreatment levels could be measured, independent of race and diet. 4. In the Caucasian non-vegetarian group 1,25 dihidroxyvitamin D levels, the most active metabolite of vitamin D, were also measured and remained unaltered despite a substantial fall in 25-hydroxy substrate. 5 The acute fall in 25-hydroxyvitamin D concentration with a maintained level of 1,25 dihidroxyvitamin D may represent the early changes of drug-induced osteomalacia.
1 The effects of single oral doses of 10 mg and 20 mg metoclopramide have been compared to placebo in six normal male volunteers. 2 The drug did not significantly increase the rate of gastric emptying as measured by ethanol absorption. 3 Sedation during the absorption of ethanol was only observed 1 h after the 20 mg oral dose of metoclopramide (P less than 0.05). 4. Akathisia, a central nervous system side effect of metoclopramide, occurred only in subjects who had peak plasma concentrations above 100 ng/ml. 5 It has not been possible to define a concentration-effect relationship for the action of metoclopramide on the stomach and comparison with previous results after intravenous dosing suggests that the route of administration is of major importance in determining the action of this drug.
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1 Pharmacokinetic and concentration-effect studies have been carried out following intravenous injection of 10 mg metoclopramide hydrochloride to seven normal male volunteers. 2 It is proposed that a two-compartment model adequately describes the disposition of the drug which is rapidly distributed (T1/2alpha = 4.9 +/- 1.1 min) and eliminated (T1/2beta = 165.7 +/- 20.2 min). Total body plasma clearance of the drug is high (10.9 +/- 1.5 ml min-1 kg-1) and approximates to liver plasma flow. 3 Metoclopramide i.v. increases gastric emptying as measured by an ethanol absorption test (P less than 0.005). The duration of this effect is at least 3 h. 4 Ethanol given after i.v. metoclopramide administration produces significant sedation during the first hour and at 3 h (P less than 0.001). 5 The effect of metoclopramide on gastric emptying, and the degree of sedation induced by ethanol would appear to be related to plasma metoclopramide concentration. 6 Metoclopramide increases serum prolactin to 59 +/- 5.8 microgram/1 at 30 min after injection. There is a linear relationship (r = 0.809) between serum prolactin increase and plasma metoclopramide concentration.
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