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Biomedical subjects

P J de Schepper

Publications and source records attributed to P J de Schepper.

13 recordsLinked to original sources
PubMed1994

Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.

5-Lipoxygenase-Activating Proteins↗
PubMed1992

Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use.

In 12 healthy volunteers, paracetamol pharmacokinetics were compared following administration of 1 g propacetamol HCl given intravenously over a 15-min period and 500 mg paracetamol given orally. Mean +/- SD total AUC (microgram/ml.h) following the iv formulation was significantly (P < 0.01) greater than following oral paracetamol (25.53 +/- 4.27 vs 21.04 +/- 4.49) corresponding to a mean oral bioavailability of paracetamol of 82.2 +/- 9.4%. Between 1 and 2 h after administration, paracetamol plasma concentrations became very similar following both formulations. In another study, 2 g propacetamol HCl was given both as a 15-min infusion and as a 2-min bolus injection to six healthy volunteers. Contrary to mild to moderate local discomfort experienced during the 2-min bolus injection, the 15-min infusion was well tolerated without any complaints reported.

Acetaminophen↗
PubMed1986

Altered pharmacokinetics of oral flecainide by cimetidine.

A potential kinetic interaction between cimetidine and flecainide has been studied in eight healthy males receiving flecainide (200 mg) orally on three occasions: before any treatment and on day 2 and day 7 of 8 days' cimetidine maintenance treatment at 1 g daily. Six days pretreatment with cimetidine induced the following changes in flecainide kinetic parameters: average tmax was prolonged from 1.8 h to 3.6 h and total AUC increased significantly from 4779 to 6131 ng ml-1 h. Plasma elimination half-life and renal clearance were not significantly altered. The fraction of flecainide dose excreted unchanged in urine rose significantly from 31 to 38%. The observed interaction can be explained by an increase in bioavailability or, more probably, by a decrease in biotransformation of flecainide in the presence of cimetidine.

Administration, Oral↗
PubMed1985

The influence of diflunisal on the pharmacokinetics of oxazepam.

Single dose pharmacokinetics of oxazepam, 30 mg, have been studied in six healthy male volunteers in the absence of diflunisal and during continuous treatment with diflunisal 500 mg twice daily. During diflunisal treatment, peak plasma concentration of oxazepam significantly decreased from 387 +/- 18 ng ml-1 (mean +/- s.e. mean) to 241 +/- 10 ng ml-1 and total area under the plasma concentration-time curve (AUC) significantly decreased from 5536 +/- 819 ng ml-1 h to 4643 +/- 562 ng ml-1 h. The AUC of oxazepam glucuronide significantly increased from 4771 +/- 227 ng ml-1 h to 8116 +/- 644 ng ml-1 h and its elimination half-life increased from 10.0 +/- 0.6 h to 13.0 +/- 1.0 h. Renal clearance for oxazepam glucuronide was significantly reduced from 74 +/- 2 ml min-1 to 46 +/- 3 ml min-1. In vitro, diflunisal, at concentrations of 125 to 1000 micrograms ml-1, significantly displaced oxazepam from its plasma protein binding, the free fraction of oxazepam increasing by 28 to 56%. The free fraction of oxazepam glucuronide, ex vivo, increased by 49 +/- 5% (n = 3) during concomitant diflunisal treatment. These data suggest that the observed interaction between oxazepam and diflunisal results from a presystemic displacement of oxazepam from its plasma protein binding sites by diflunisal and from an inhibition of the tubular secretion of oxazepam glucuronide by the glucuronides of diflunisal.

Adult↗
PubMed1982

[Pharmacokinetics of mezlocillin. Comparison with ampicillin and influence of probenecid (author's transl)].

In a randomized cross-over study 10 healthy male volunteers received a single 1 g dose of 6-[R]-2-3-methylsulfonyl -2- oxo-imidazolisine -1- carboxamido) -2- phenyl-acetamido]-penicillanic acid sodium salt (mezlocillin) and of ampicillin, either intravenously or intramuscularly. Following the intravenous loading dose, mean peak serum levels of 101 micrograms/ml for mezlocillin and 91.5 micrograms/ml for ampicillin were recorded. The ultimate half-life t 1/2 of mezlocillin (46.4 min) was slightly shorter than that of ampicillin (52.4 min). Similarly, the total volume of distribution of mezlocillin (24.1 l) was slightly inferior to that of ampicillin (29.4 l). The proportions of the dose administered recovered in the urine of 24 hours were 50.4 % for mezlocillin and 69.9 % for ampicillin. The total clearances of the two antibiotics were not significantly different, but the renal clearance of mezlocillin (186.6 ml/min/1.73 m2) was significantly lower than that of ampicillin (309.5 ml/min/1.73 m2). Following intramuscular injection, the mean peak serum levels obtained were 15.6 microgram/ml with mezlocillin and 15.1 micrograms/ml with ampicillin. The half-lives of the antibiotics were 50.0 min and 57.2 min respectively. The bioavailable fractions of mezlocillin and ampicillin, as measured from the areas under the serum concentration curves wer 63 % and 75 % respectively of the values determined after intravenous injection. The oral administration of 1 g probenecid one hour before an intramuscular injection of mezlocillin increased the peak serum level and area under the curve by 65 % and decreased the total clearance, renal clearance and apparent volume of distribution by 38 %, 52 %, and 35 % respectively. However, the ultimate half-life was not significantly altered (50.5 min without, and 52.0 min with probenecid).

Adult↗
PubMed1982

Ranitidine: single dose pharmacokinetics and absolute bioavailability in man.

1 Ranitidine single dose pharmacokinetics and absolute bioavailability have been studied in five healthy male volunteers. Following an overnight fast, 150 mg was given intravenously as a bolus injection or orally as a tablet formulation to each subject on separate occasions. 2 Following intravenous administration, plasma levels declined biexponentially. The mean (+/- s.d.) distribution half-life (t 1/2 alpha) was 6.6 +/- 1.6 min; plasma half-life (t 1/2 beta) was 1.7 +/- 0.2 h; the volume of distribution (V) was 96 +/- 9 1; total body clearance (CL) was 647 +/- 94 ml/min and renal clearance (CLR) 520 +/- 123 ml/min. 3 Following oral administration plasma levels showed a bimodal pattern with a first peak at 1.1 +/- 0.4 h and a second peak at 3 +/- 0 h. The absolute availability was 60 +/- 17%. The plasma half-life (t 1/2) of 2.3 +/- 0.4 h was significantly longer (P less than 0.05) after oral than after i.v. administration. 4 Renal excretion of unchanged ranitidine accounted for 79 +/- 9% of the dose after i.v. administration and for 27 +/- 7% after oral administration. 5 Our results suggest a more extensive biotransformation of ranitidine and biliary excretion of metabolites after oral administration while i.v. administration ranitidine is preferentially excreted unchanged in the urine.

Administration, Oral↗
PubMed1979

Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man.

1 Fluphenazine (1,2-ethanol 14C) was administered to seven human subjects as the dihydrochloride and as the enanthate and decanoate esters. 2 The subjects had previously been treated with fluphenazine injections for at least 6 months. 3 Fluphenazine was separated from its radioactive metabolites by selective solvent extraction. Plasma concentrations were measured for up to 21 days after dosing. 4 The preparations showed differences in peak concentrations, times of the peaks and half-times of the elimination phase. The longest half-times occurred with the decanoate and the shortest with the dihydrochloride. 5 It is postulated that the differences in kinetics relate principally to the release of the compound from the site of injection. 6 There was no evidence for presence of the esters in plasma, urine or faeces.

Adult↗
PubMed1979

Effect of aluminum hydroxide on diflunisal absorption.

1 The effect of aluminum hydroxide on the oral absorption of diflunisal was studied in healthy subjects. 2 Relative bioavailability of the oral diflunisal dose (500 mg) was estimated by comparison of the areas under plasma concentration versus time curves, and comparison of the amount of drug (unchanged + glucuronides) excreted in the urine. 3 From the AUC-method, a relative bioavailability of 0.60 was calculated. A similar value (F = 0.63) was obtained from the urinary excretion data. 4 The results indicate that co-administration of aluminum hydroxide reduces the bioavailability of oral diflusinal by about 40%.

Aluminum Hydroxide↗
PubMedDate not supplied

Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog, and rat.

The succinimidoethyl (Sm) and pivaloyloxyethyl (P) esters of methyldopa were evaluated as progenitors of the latter. Experiments in spontaneously hypertensive (SH) rats and humans demonstrated that a radioactive dose of progenitor was well absorbed. The metabolism of these progenitors appeared to be comparable in the SH rat; the urinary excretion of [3H]methyldopa was similar after oral administration of [3H]Sm or [3H]P. In humans the levels of [3H]methyldopa were higher in the urine following administration of [3H]P. Apparently Sm was more resistant than P to extrahepatic esterase action in man (and dog). In man the catechol nucleus of Sm was apparently conjugated prior to hydrolytic cleavage to release conjugated [3H]methyidopa. The progenitors possessed similar antihypertensive properties in the SH rat but preliminary results in humans suggested that Sm possessed less antihypertensive potency than P.

Adult↗