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Biomedical subjects

L F Chasseaud

Publications and source records attributed to L F Chasseaud.

At least 73 records · Page 4Linked to original sources
PubMed1983

Biotransformation of lofexidine in humans.

1. Concentrations of unchanged drug and patterns of radioactive components in urine have been determined by h.p.l.c. following single oral doses of [14C]lofexidine hydrochloride (0.32 mg) to six human subjects. 2. A mean of 12% of the administered dose was excreted in urine as unchanged lofexidine, but the wide range (5-20% dose) indicated significant intersubject variation in the extent of biotransformation. This drug would appear to be metabolized more extensively than the related anti-hypertensive agent, clonidine. 3. The principal metabolite of lofexidine was 2,6-dichlorophenol, which was apparently excreted in urine as two O-glucuronic acid conjugates. The same two metabolites were also the main 14C components circulating in plasma at peak 14C concn. Formation of the phenol from lofexidine probably involved direct O-dealkylation rather than stepwise degradation of the side-chain. 4. Patterns of 3H components in the urine of rats and dogs after oral administration of [3H]lofexidine hydrochloride (0.1 mg/kg) were generally similar to those in human urine.

Adult↗
PubMed1983

Bioavailability of isosorbide dinitrate and its two mononitrate metabolites from sustained-release formulations.

Plasma concentrations and bioavailability of isosorbide dinitrate (ISDN) and its active metabolites isosorbide 2-mononitrate (2-ISMN) and isosorbide 5-mononitrate (5-ISMN) from two sustained-release formulations and one standard-release formulation of isosorbide dinitrate were compared. Means of peak drug concentrations of ISDN, 2-ISMN, and 5-ISMN after administration of the 20-mg sustained-release formulation were 5.5, 24.4, and 129.1 ng/ml, respectively, at 3.1, 4.2, and 4.5 h; after the 40-mg sustained-release formulation, they were 10.9, 44.0, and 214.5 ng/ml, respectively, at 4.2, 6.3, and 6.7 h; and after the 20-mg standard formulation, they were 19.1, 34.7, and 159.2 ng/ml, respectively, at 0.5, 1.0, and 1.5 h. As might be expected, peak concentrations and their times of occurrence were statistically significantly different when results from the sustained-release formulation were compared to those from the standard formulation. Plasma drug concentrations were detectable for longer after administration of the sustained-release formulations. The extent of bioavailability of ISDN, 2-ISMN, and 5-ISMN from the three formulations as estimated from the areas under the plasma drug concentration - time curves were not statistically significantly different (p greater than 0.05). The ratios for relative drug bioavailability from the respective formulations were similar whether ISDN, 2-ISMN, or 5-ISMN data were used for calculation. Reasons are discussed for the biphasic decline of plasma ISDN concentrations (half-lives 26 min and 5.1 h) obtained after administration of the standard-release formulation.

Adolescent↗
PubMed1983

Newer aspects of the pharmacokinetics of organic nitrates.

Plasma drug and metabolite concentrations were measured after single oral doses of 40 mg sustained-release 14C-isosorbide dinitrate to humans. The bioavailability of isosorbide dinitrate from this sustained-release formulation was about 90% of that from a standard formulation. The pharmacokinetics of isosorbide-5-mononitrate were studied in humans after intravenous infusion (8 mg/h) and oral doses of 20 mg. The systemic availability of the drug after oral doses was 93%, its systemic clearance was 127 ml/min, its volume of distribution was 48.5 liters and its half-life was 4.4 h.

Biological Availability↗
PubMed1983

The effect of intravenously administered phosphocreatine on ATP and phosphocreatine concentrations in the cardiac muscle of the rat.

Following intravenous administration of 32P-phosphocreatine (50 mg/kg) or an equimolar mixture of creatine + 32P-phosphate (equivalent to 50 mg/kg phosphocreatine) to rats, and examination of an extract of cardiac muscle by HPLC, the proportion of radiolabelled adenosine triphosphate (ATP; up to 3%) was similar in each treatment group at 120 min after dosing. Mean concentrations of ATP in the cardiac muscle were increased significantly during this time (to 3.1 mumol/g) after intravenous administration of 32P-phosphocreatine compared with those in control rats (2.5 mumol/g) and in rats dosed with creatine + 32P-phosphate mixture (2.6 mumol/g). Phosphocreatine concentrations in cardiac muscle of phosphocreatine-treated rats were also increased (2.3 mumol/g) significantly after 120 min compared with controls (1.7 mumol/g), but were unchanged after 30 min. Mean concentrations of phosphocreatine in rats receiving a creatine + phosphate mixture were slightly reduced (1.3 and 1.5 mumol/g after 30 min or 120 min, respectively) compared with controls. The elevation of tissue ATP and phosphocreatine levels may be involved in the protective effect provided by exogenous phosphocreatine against anoxia in isolated cardiac muscle.

Adenosine Triphosphate↗
PubMed1983

[Pharmacokinetics of 14C-isosorbide dinitrate after administration in various sustained-release formulations].

To study the influence of various in vitro release rates and of coadministration with food on bioavailability of isosorbide dinitrate (ISDN; isoket retard 40) and its mononitrate metabolites from sustained-release formulations the pharmacokinetics of two experimental batches of tablets with different release rates containing 40 mg 14C-ISDN each were studied in six human volunteers. One of the formulations was not only administered after fasting but aslo with a standard meal. In all cases approx. 80% of the administered radioactivity were recovered in the urine and 5% in the faeces during 3 days demonstrating extensive absorption. Any influence of release rates or food on absorption rates could not be detected. When administered after fasting either formulation was bioequivalent. Coadministration of a meal enhanced ISDN plasma levels in some subjects although no statistically significant difference in extent of bioavailability was observed. Availability of the mononitrates was unaffected by food.

Adult↗
PubMed1983

Tolmetin uptake into inflamed tissue in the rat.

Concentrations of the antiinflammatory agent tolmetin have been measured by HPLC in inflamed and non-inflamed rat tissues after oral administration of tolmetin sodium dihydrate in solution (100 mg free acid/kg) and after topical administration of tolmetin (Tolectin gel, 1 g of a 5% gel, 250 mg free acid/kg). After oral administration of tolmetin, there was marked localisation of the drug in inflamed rat paws. Concentrations of tolmetin were significantly greater in inflamed paws than those in non-inflamed paws at each time studied (e.g. at 3 h after dosing, inflamed paw 30.5 micrograms/g, non-inflamed paw 14.9 micrograms/g). After a single topical application of tolmetin gel to the shaved backs of rats, tolmetin was well absorbed percutaneously into the non-inflamed dorsal muscle. After repeated topical application of tolmetin gel to the shaved backs of rats, daily for 4 consecutive days, concentrations of tolmetin (total micrograms/paw) similar in inflamed paws and in non-inflamed paws. After topical administration of tolmetin gel to rat paws, tolmetin was transported from treated paws to untreated paws, e.g. from non-inflamed paws to inflamed paws and vice versa. These studies showed that tolmetin applied topically reaches inflamed tissues in concentrations that exceed those in plasma.

Administration, Topical↗
PubMed1982

Bioavailability of indomethacin from two multiple-units controlled-release formulations.

Two multiple-units controlled-release indomethacin capsule formulations containing enteric-coated pellets were bioequivalent to a standard capsule formulation (taken as the reference) in respect of extent of bioavailability in a crossover study with normal human subjects. However, drug absorption from the enteric-coated pellet formulations was slower, when compared to that from the standard reference capsule. The standard reference capsule released 85% of its drug content in vitro during 10 min at pH 6.5 and 98% during 1 h at pH 7.5. On enteric-coated pellet capsule formulation (I) released 77% during 1 h at pH 6.5 and the other (II) released 10% during 1 h at pH 6.5. Release of drug from each capsule of enteric-coated pellets was complete during 1 h at pH 7.5. Although differences in areas under the plasma indomethacin concentration-time curves were not significantly different, the peak plasma levels and the times of their occurrence indicated that the absorption rates of indomethacin decreased in the order, reference formulation greater than pellet formulation I greater than pellet formulation II, which was the same rank order as that of their dissolution rates in vitro. The data indicated that multiple units controlled-release formulations represent a reliable and reproducible source of indomethacin, which by avoiding extremes of local or systemic drug concentrations also should be better tolerated by individuals susceptible to unwanted gastrointestinal and centrally-mediate side-effects.

Adult↗
PubMed1982

Preparation and properties of primary maintenance cultures of adult rabbit hepatocytes.

Static and rotary cultures of adult rabbit hepatocytes can be produced reproducibly following their isolation by means of a simplified, inexpensive recycling perfusion system. Light and electron microscopic examination of the cultures showed that these hepatocytes retained the morphological characteristics of fully differentiated hepatic parenchymal cells for up to 5 days in static culture and for up to 10 days in rotary culture, after which time they progressively degenerated and were replaced by other cell types. These hepatocytes exhibit several major metabolic functions characteristic of liver in vivo, including bromsulphthalein uptake, albumin synthesis, bilirubin conjugation, lipid synthesis, urea production and responsiveness to insulin. The xenobiotic metabolising capability of the cultured hepatocytes was much more stable than that of rat hepatocytes and the mixed function oxidase activity was typical of cytochrome P-450, rather than cytochrome P-448 as indicated by the metabolite profiles of biphenyl, aminopyrine, ethylmorphine, benzo[a]pyrene and 7-ethoxycoumarin. Treatment with phenobarbitone led to drug metabolising enzyme induction: SKF525A and alpha-naphthoflavone were effective inhibitors of drug metabolising activity.

Ampyrone↗
PubMed1982

The effects of dimethylnitrosamine and allyl alcohol on primary maintenance cultures of adult rabbit hepatocytes.

Cultures of adult rabbit hepatocytes have been used to study the early toxic effects of 2 model hepatotoxins, dimethylnitrosamine and allyl alcohol. Leakage of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase into the cell culture medium was a sensitive indicator of plasma membrane damage by these compounds and a dose-response relationship was observed. By contrast, gamma-glutamyltranspeptidase and alkaline phosphatase were insensitive markers. The effects of dimethylnitrosamine were slower to develop. Dimethylnitrosamine also produced a dose-related inhibition of protein synthesis after 4 h, a decrease in NADPH diaphorase and an increase in non-specific esterase after 20 h. Dimethylnitrosamine, unlike allyl alcohol, caused extensive disruption of ribosome association with the endoplasmic reticulum.

1-Propanol↗
PubMed1982

Comparative pharmacokinetics of frusemide in female rhesus monkeys, cynomolgus monkeys and baboons.

1. The pharmacokinetics of frusemide have been compared in 3 non-human primate species after single intravenous dose of 3 mg/kg of the drug. 2. Peak mean plasma concentrations of frusemide were 31.6, 33.6, 43.6 micrograms/ml in the rhesus monkey, cynomolgus monkey and baboon respectively, and concentrations declined with a half-life of about 20 min. 3. There were no notable differences in the pharmacokinetic parameters estimated from either a one-compartment or two-compartment open model. 4. There were statistically significant species-related differences in clearance, half-lives and volumes of distribution adjusted for bodyweight. 5. The pharmacokinetics of frusemide in the cynomolgus monkey are closer to those in man than are those in the rhesus monkey, the baboon or other commonly used laboratory animal species.

Animals↗
PubMed1982

The effect of dose and vehicle on early tissue damage and regenerative activity after chloroform administration to mice.

The relationship between the acute toxicity of orally-administered chloroform and its long-term tumorigenic potential was studied in male mice of the CFLP outbred Swiss albino mouse strain. A single dose of approximately 18 mg CHCl3/kg had no detectable acute toxic effect on the liver or kidneys and did not stimulate regenerative activity, whereas both toxicity and subsequent tissue regeneration were observed with single doses of about 60 mg/kg or higher. The severity of the toxic effects and regenerative changes was greater when corn oil was used as a vehicle for chloroform than when the vehicle was a toothpaste base. In earlier long-term studies in mice of the same strain, kidney tumours occurred in males given 60 mg/kg/day throughout life but not in mice given 17 mg/kg/day. The tumour response was greater when the 60-mg/kg/day dose was given in an oily vehicle than when it was given in toothpaste. The findings are consistent with the hypothesis that early acute toxic change and subsequent repair are a sine qua non for tumorigenesis in the kidney and liver in response to chloroform.

Animals↗
PubMed1982

A novel conjugate as a major metabolite of bromperidol in man.

The major urine metabolites of the neuroleptic drug, bromperidol, after oral doses to rats and dogs are p-fluorophenylacetic acid and its glycine conjugate resulting from oxidative N-dealkylation. While the same metabolites were also detected in human urine, also present was a major unknown component representing 50% of the total urine metabolites, which apparently was not formed by rats and dogs to any extent. Mass spectroscopic investigations a substituent attached to the tertiary hydroxyl group. The mass spectrum of the metabolite after trifluoroacetylation was consistent with an O-glucofuranosiduronolactone conjugate of bromperidol.

Biotransformation↗
PubMed1982

Effect of the triazolobenzodiazepine estazolam on hepatic drug-metabolizing enzyme activity in rats.

Oral doses of the sedative/hypnotic estazolam (500 mg kg-1 day-1) to rats for 21 days caused statistically significant increases in liver weight, ascorbate excretion, cytochrome P-450 concentrations, and in aniline hydroxylase, ethylmorphine N-demethylase and glutathione S-transferase activities, as did approximately equivalent doses of flurazepam hydrochloride. Histologically, the centrilobular hepatocytes were enlarged. Some of these parameters were also increased after doses of estazolam of 100 mg kg-1 day-1, but not after 5 mg kg-1 day-1, which is about 50-fold greater than a clinical dose. Estazolam was a much less potent enzyme inducer than phenobarbitone under the conditions of these studies.

Animals↗
PubMed1982

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man.

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.

Administration, Oral↗