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L F Chasseaud

Publications and source records attributed to L F Chasseaud.

At least 37 records · Page 2Linked to original sources
PubMed1991

Dose-proportional pharmacokinetics of cefepime in rats.

Cefepime (BMY-28142) is a new parenteral cephalosporin antibiotic with excellent activity against a broad-spectrum of clinically important pathogens resistant to other new cephalosporins. A single bolus dose of 10, 20 or 40 mg/kg cefepime was given i.v. to male and female Sprague-Dawley rats from which blood and urine samples were collected. For statistical reasons, pharmacokinetic parameters (AUC, Kel) were derived by fitting an exponential curve to the plasma concentrations; subsequently, contrasts were made between the different doses for AUC and Kel and, in addition, plasma concentrations observed after the first sampling time (Cmax). Cmax and AUC appeared to be linearly related to the administered dose in both males and females. The dose increased in the ratio 1:2:4 and mean Cmax in male and female rats increased in the ratio 1:2.3:4.1 and 1:2.3:4.4 respectively; similarly, AUC increased in the ratio 1:2.2:4.3 and 1:2.0:4.2 respectively. Deviations from linearity and proportionality were not significant (P0.05). The systemic clearance of cefepime in rats was 2.3 ml/min. The volume of distribution was about 60 ml and cefepime appears to be selectively distributed into the extracellular water. Plasma concentrations declined monoexponentially with a mean half-life of 15-20 min which did not significantly change with increasing doses. The renal clearance of cefepime was 1.8 ml/min and approximately 80% of the dose was excreted in the urine unchanged; renal excretion of cefepime is the major route of elimination in rats. The elimination and distribution characteristics of cefepime in rats were similar to those observed in man.

Animals↗
PubMed1990

Determination of ximoprofen and its metabolites in human urine by high-performance liquid chromatography with ultraviolet absorbance detection.

A simple, sensitive and selective method for the determination of ximoprofen and its keto and hydroxy metabolites in human urine has been developed using high-performance liquid chromatography in the reversed-phase mode. The limit of reliable determination of ximoprofen and each of its metabolites in urine is about 1 microgram/ml (4 nmol/ml). The method has been applied to urine samples obtained from human volunteers after administration of single intravenous doses of 30 mg of ximoprofen and about 70% dose was accounted for in terms of these compounds and their glucuronic acid conjugates.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Determination of benzydamine and its N-oxide in biological fluids by high-performance liquid chromatography.

A simple, sensitive and selective method for the determination of benzydamine in human plasma and urine, and for benzydamine N-oxide in urine, has been developed using high-performance liquid chromatography in the reversed-phase mode. The limit of reliable determination of benzydamine in plasma was 0.5 ng/ml and that in urine 1 ng/ml; the limit of reliable determination of benzydamine N-oxide in urine was 50 ng/ml. The method has been successfully applied to the analysis of these compounds in biological fluids after administration of intravenous and oral doses of benzydamine to human volunteers.

Benzydamine↗
PubMed1990

The metabolic fate of 14C-ximoprofen in rats, baboons and humans.

1. The metabolic fate of 14C-ximoprofen was compared in rat (2 mg/kg), baboon (2 mg/kg) and human (approx. 0.4 mg/kg). An oral dose was well absorbed in all three species as indicated by urinary excretion of 80%, 86% and 94% dose respectively in 5 days: excreted in the faeces were 14%, 2% and 2% dose respectively. 2. Total 14C in plasma reached peak concentrations at 1-1.5 h in humans and earlier in animals. In humans, plasma 14C was initially associated mainly with unchanged drug which declined with a half-life of about 2 h (plasma 14C t1/2 about 8 h; cf. about 6 h in animals). 3. Tissue 14C concentrations in rats were generally similar to those in baboons at 1 h after dosing, decreasing substantially at later times. The distribution of 14C was consistent with that of a compound readily eliminated. 4. The major biotransformation products of ximoprofen were formed by hydrolysis to the keto-analogue followed by reduction to the hydroxy-analogue and conjugation of these two compounds. The same major metabolites were detected in urine of rat, baboon and humans but there was (a) complete biotransformation of ximoprofen in the rat, (b) an apparent difference in the nature of the conjugated component(s) in rat urine and those in baboon and human urine, (c) only one hydroxy-analogue detected in human urine but two such compounds in animal urine as indicated by mass spectrometry. 5. In human plasma at peak concentrations, the relative importance of circulating components was ximoprofen greater than keto-analogue greater than hydroxy-analogue, whereas in the plasma of the animal species this order was reversed, consistent with the more extensive biotransformation of ximoprofen observed in rat or baboon.

Adult↗
PubMed1989

Absorption of amlodipine unaffected by food. Solid dose equivalent to solution dose.

The oral bioavailability of amlodipine in healthy volunteers was compared in two separate studies after solution and capsule doses, and after capsule doses in fed and fasting states. The bioavailability of amlodipine was equivalent both in terms of rate and in extent of absorption between solution and capsule doses and in the fed and fasting states.

Adult↗
PubMed1987

Isosorbide 5-mononitrate pharmacokinetics.

Isosorbide 5-mononitrate differs from other clinically used organic nitrate vasodilators because of its almost complete oral absorption, the low intersubject variability in its plasma concentrations and pharmacokinetic parameters, its relatively long half-life and its lack of active metabolites. The drug does not appear to be bound to plasma proteins and it is metabolized primarily by denitration and conjugation. Its clearance is 127 ml/min, volume of distribution 48.5 litres and half-life 4.4 h. Its pharmacokinetics are linear over the dosage range likely to be used clinically. Sustained-release formulations of the drug could prove suitable for once-a-day administration. In disease states (cardiac, renal or hepatic), the plasma concentrations and pharmacokinetics of the drug appear to be similar to those in healthy subjects.

Humans↗
PubMed1987

Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog.

1. The metabolic fate of 14C-benzarone in the rat and dog has been compared to that in human subjects. An oral dose was well-absorbed in all three species. However, the 14C excretion patterns differed: humans (100 mg) excreted means of 73 and 19% dose in the urine and faeces respectively, whereas the rat (2 mg/kg) and dog (0.5 mg/kg) excreted greater than 80% in the faeces, mostly during the first 48 h. 2. Much of the faecal 14C was attributable to 14C excreted in the bile which amounted to 59% in the 7 h bile collected from an intravenously dosed dog, and a mean of 72% in the 24 h bile of orally dosed rats. Enterohepatic circulation of 14C was demonstrated in rats. 3. Total 14C in human plasma reached peak concentrations between 1-2 h and declined relatively rapidly, to about 10% of this value within 24 h. Unchanged benzarone was not detected in plasma (less than 25 ng/ml), even after a 400 mg dose, but conjugated benzarone was--accounting for about 10% of the peak concentration of 14C. In the dog, by contrast, conjugated benzarone accounted for about 50% of the peak concentration of 14C of 0.96 microgram equiv./ml at 1 h. The extent of binding of benzarone to human plasma proteins (greater than 99%; in vitro was slightly greater than that (greater than 96%) of total 14C (ex vivo, representing metabolites). 4. Examination of metabolite profiles by h.p.l.c. suggested that in the rat and dog, at least 70% absorbed dose was eliminated by direct conjugation, whereas in humans at least 70% was hydroxylated before conjugation, mainly with glucuronic acid. Hydroxylation occurred in the benzofuran ring and/or the ethyl side-chain. The principal urinary metabolite in humans was the conjugate(s) of the 1-hydroxylated ethyl side-chain derivative (mean 26% dose).

Adult↗
PubMed1987

The metabolism and pharmacokinetics of 14C-cetirizine in humans.

This study investigated the metabolism and pharmacokinetics of cetirizine, a new H1-receptor antagonist. Single oral doses of 14C-cetirizine dihydrochloride (10 mg) in aqueous solution were administered to six healthy male volunteers. The drug was rapidly absorbed: The peak mean concentration of radioactivity (359 ng-equivalents/mL) and of unchanged drug (341 ng/mL) were achieved within one hour. Mean concentrations of cetirizine declined biexponentially and had a mean elimination half-life of 7.4 hours. The drug was excreted quite rapidly, with 60% of the dose recovered in the 24-hour urine. An additional 10% was excreted in urine over the next four days. Approximately 10% of the dose was excreted in feces over the five-day study period. The dose was excreted mainly as the unchanged drug. Examination of the radioactive compounds present in the plasma, and excreted in the urine and feces indicate that there is little metabolism of cetirizine. One minor metabolite, formed by oxidative O-dealkylation of the cetirizine side chain, was detected in plasma and feces.

Adult↗
PubMed1986

Pharmacokinetics and metabolism of 14C-tinidazole in humans.

Following intravenous infusion of 800 mg of 14C-tinidazole during 30 min to two human subjects, a mean of 44% of the dose was excreted in urine during the first 24 h, increasing to 63% of the dose during five days: 12% of the dose was excreted in the faeces, indicating the possible involvement of biliary excretion and other secretory processes in the disposition of tinidazole. At 6 min after the end of the infusion, the mean plasma tinidazole concentration was 12 mg/l. Tinidazole was a major component in 0-120 h urine (about 32% of urinary 14C): the major metabolite in the 0-12 h urine examined was ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone (about 30% urinary 14C), the product of hydroxylation and nitro-group migration. These compounds were also present in the faeces. A minor urinary metabolite was 2-hydroxymethyltinidazole (about 9% urinary 14C), which was also present in plasma. The mean pharmacokinetic parameters obtained for tinidazole were similar to those reported in the literature; total clearance 51 ml/min, renal clearance 10 ml/min, volume of distribution 501 and half-life 11.6 h.

Adult↗
PubMed1986

The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily.

Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half-life of 34 h, mean clearance of 7 ml min-1 kg-1 and a mean apparent volume of distribution of 21 l kg-1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half-life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.

Administration, Oral↗
PubMed1986

Pharmacokinetics of the bronchodilator tulobuterol in man after repeated oral doses.

Plasma levels and elimination half-life of tulobuterol, a new beta-adrenergic agonist, were determined in ten healthy male volunteers after repeated dosing with 2 mg, twice daily, for seven days. Peak plasma levels attained (2.8 +/- 0.8 ng/ml), the time to peak plasma concentration (1.0 +/- 0.3 hr) and the elimination half-life (2.4 +/- 0.4 hr) were generally unchanged from the first to the final study dose. This suggests that tulobuterol does not accumulate in plasma after repeated administration of a dose regimen known to be clinically effective.

Administration, Oral↗
PubMed1985

Reasons for monitoring kinetics in safety evaluation studies.

Studies of the toxicity of a potential new drug form the basis of its preclinical safety evaluation and it is important that these toxicity studies are designed and conducted in a rational manner to permit the reliable interpretation and extrapolation of the resulting data to man. It is proposed that these objectives are more likely to be met with the support of pharmacokinetic data. Generally, toxicity studies include four groups of animals, a control group and three treated groups receiving low, intermediate and high dose levels respectively. In order to assist in the proper selection of appropriate dose levels and to increase the usefulness of the data obtained from toxicity studies, information on the following should be known. Relationship between dose level and the extent of absorption of the test compound. Effect of repeated (chronic) doses on the pharmacokinetics of the test compound. Relationship between the age of the animal and pharmacokinetics of the test compound. Relationship between the dose regimen used clinically and those used in toxicity studies.

Age Factors↗
PubMed1985

Metabolism and pharmacokinetics of the dihydropyridine calcium antagonist, ryosidine, in man.

The metabolic fate of [14C]ryosidine (ryodipine) has been investigated after oral administration to human subjects (by capsule), and to rats and dogs (in solution). The excretion patterns of 14C were similar for all three species: about 50% dose was excreted in urine, mainly in 24 h, but a proportion was excreted slowly, particularly by humans. Absorption in man appeared to be less than in the animal species, probably as a result of the capsule dosage form used. Mean concentrations of total 14C in human plasma reached a peak value of 0.41 microgram equiv./ml at four hours and declined biphasically thereafter (mean terminal t1/2 = 28 h). Unchanged ryosidine was only detected in plasma from two to six hours (mean t1/2 = 80 min), and never accounted for more than 5% of the plasma 14C. The extent of binding of ryosidine to the plasma proteins (in vitro) was similar (greater than 90%) to that of total 14C (in vivo; mainly metabolites). Less than 0.5% of the dose to human subjects was excreted via the kidneys as unchanged ryosidine, whereas the bulk of the extractable faecal 14C was in the form of unchanged drug and presumably represented unabsorbed material. The principal routes of biotransformation of ryosidine in all three species involved oxidative aromatization of the 1,4-dihydropyridine ring, followed by ester hydrolysis, O-dealkylation, hydroxylation of an alpha-methyl group (and lactonization) and some glucuronidation, although quantitative interspecies differences were apparent.

Administration, Oral↗