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Biomedical subjects

L F Chasseaud

Publications and source records attributed to L F Chasseaud.

At least 55 records · Page 3Linked to original sources
PubMed1985

A novel metabolite of tinidazole involving nitro-group migration.

After oral doses to dogs of 14C-tinidazole, a 5-nitroimidazolyl antiprotozoal compound, a major and previously unidentified radioactive metabolite was isolated from urine and shown by FAB mass spectrometry and n.m.r. spectroscopy to be ring-hydroxylated. The exact identity of this metabolite was established by X-ray diffraction analysis as ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone. The apparent migration of the nitro group from the 5 position in the parent drug to the 4 position in the metabolite is a novel metabolic route.

Animals↗
PubMed1985

Bioavailability studies of etofibrate in rhesus monkeys.

Etofibrate (Lipo-Merz) is a newer antilipaemic agent that contains the nicotinic and clofibric acid moieties joined together through a diester link with ethylene glycol. The bioavailability of these moieties in etofibrate was compared to that from equimolar amounts of these drugs administered alone to rhesus monkeys (clofibric acid 354 mg, nicotinic acid 203 mg). For this comparative purpose, analytical methods were chosen which converted etofibrate and its initial metabolites into clofibric and nicotinic acid. Following this treatment, the rate and extent of bioavailability of unchanged nicotinic acid from etofibrate was significantly lower (P less than 0.01) than that from nicotinic acid alone. Mean peak whole blood levels of 11.9 micrograms/ml at 2.8 h and 35.3 micrograms/ml at 1.3 h, respectively, occurred after administration of etofibrate and nicotinic acid alone. The extent of bioavailability of clofibric acid hydrolysed from etofibrate was not significantly different (P greater than 0.05) from that from clofibric acid alone. However, mean peak plasma levels of 127.3 micrograms/ml at 3.6 h and 170.8 micrograms/ml at 2.4 h, respectively, occurred after administration of etofibrate and clofibric acid alone and were significantly different (P less than 0.01). The rates and extent of bioavailability of nicotinic acid or clofibric acid administered as a mixture were similar to that from these drugs administered alone. Thus either drug did not affect the absorption of the other in rhesus monkeys. The half-lives of nicotinic acid (in whole blood) and clofibric acid (in plasma) in rhesus monkeys when these drugs were administered alone were 9.9 h and 1.8 h, respectively.

Animals↗
PubMed1985

Pharmacokinetics of benzydamine.

Clinically, benzydamine can exert its action locally or systemically. Consequently the pharmacokinetics of this drug have been studied after its administration by several different routes. Oral doses of benzydamine are apparently well absorbed and plasma drug concentrations reach a peak fairly rapidly (e.g. 0.8 micrograms/ml after a 100-mg dose) and then decline with a half-life of about 13 h. Less than 20% of the drug is bound to plasma proteins. Assuming complete oral systemic availability, values of 193 ml/min and 213 litres respectively were calculated for the systemic clearance and volume of distribution of benzydamine. Cutaneous doses of benzydamine are more slowly absorbed and lead to peak drug levels about three-fold lower, but more persistent than those after oral administration. Although local drug concentrations are relatively large, the systemic absorption of mouthwash-gargle, vaginal and rectal doses of benzydamine is relatively low compared to oral doses: this lower absorption should greatly diminish the potential for any systemic drug side-effects when benzydamine is administered by these routes. Benzydamine is metabolized primarily by oxidation, conjugation and dealkylation.

Absorption↗
PubMed1984

Determination of bromopride in human plasma and urine by high-performance liquid chromatography.

Bromopride was measured in plasma and urine using reversed-phase high-performance liquid chromatography employing ultraviolet absorption detection. The limit of detection in plasma was 2 ng/ml, sufficient for pharmacokinetic studies of the drug. Plasma concentrations of bromopride reached mean peak levels (55 ng/ml) at 1 h after single oral doses of 20 mg and declined with a half-life of 4.9 h. Less than a mean of 10% of an oral dose was excreted unchanged in the urine. The assay could also be used to measure metoclopramide in these bio-fluids.

Chromatography, High Pressure Liquid↗
PubMed1984

Isosorbide dinitrate plasma concentrations and bioavailability in human subjects after administration of standard oral and sublingual formulations.

The bioavailability of isosorbide dinitrate from formulations containing 5, 10, and 20 mg in tablets and 10 mg in solution for oral use and 5 mg in tablets for sublingual use, has been compared. When adjusted for dose, the peak mean plasma drug concentrations after oral administration were similar (e.g., 9.2 ng/mL after a 10-mg tablet) and about one-half that obtained after sublingual administration. Drug concentrations declined monoexponentially with mean half-lives ranging from 25-36 min. The relative bioavailability of isosorbide dinitrate from the oral formulations was not significantly different (p greater than 0.05) over the dose range studied, whereas the relative bioavailability after sublingual administration was about twice as great (p less than 0.01) as that after oral administration. The plasma drug concentration-time profile after administering the 5-mg sublingual tablet was similar to that obtained after administering orally a solution containing 10 mg, indicating that the latter should be as clinically effective as the former.

Administration, Oral↗
PubMed1984

Extent of vaginal absorption of sulphated polysaccharide from A-gen 53 in the rabbit.

The vaginal absorption of a sulphated polysaccharide (SAEP), the active substance of A-gen 53+, was studied in rabbits using the 35S-labelled product. After intra-vaginal administration of 35S-SAEP, measurements of 35S in urine, faeces, plasma and tissues of the reticulo-endothelial system indicated that the small proportion of the dose (ca. 5%) absorbed from the vagina was associated mainly with inorganic material (i.e. 35S-sulphate), present as an impurity in the 35S-dose.

Absorption↗
PubMed1984

Isosorbide 5-mononitrate kinetics.

The kinetics of isosorbide 5-mononitrate (5-ISMN) were studied in 12 healthy subjects after intravenous infusion and oral doses of 20 mg. Kinetic parameters calculated by model-independent methods or by assumption of a one-compartment open model were in good agreement. Mean (+/- SD) systemic clearance of 5-ISMN was 127 +/- 21 ml/min, volume of distribution was 48.5 +/- 6.1 l, t 1/2 was 4.4 +/- 0.5 hr, and mean residence time was 6.2 +/- 0.7 hr. At the end of intravenous infusion of 5-ISMN at a rate of 8 mg/hr for 2.5 hr, mean plasma drug concentrations reached 356 +/- 39 ng/ml. Oral doses of 5-ISMN were essentially completely absorbed (93% +/- 13% systemic availability), and mean peak plasma drug concentrations of 388 +/- 70 ng/ml occurred at 0.83 +/- 0.46 hr. Mean absorption t 1/2 was 19 +/- 12 min. Unlike other vasodilator organic nitrates in clinical use, 5-ISMN is notable for its relatively long t 1/2, essentially complete oral absorption, lack of active metabolites, and low intersubject variability in kinetics.

Absorption↗
PubMed1984

Saliva concentrations of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate.

Correlations between saliva and plasma concentrations of isosorbide dinitrate (ISDN), and its active metabolites, isosorbide 2-mononitrate (2-ISMN) and isosorbide 5-mononitrate (5-ISMN) were examined. In the case of 5-ISMN (r = 0.98, P less than 0.01), saliva concentrations are probably reliable indices of the plasma concentrations of this drug and their measurement should provide a useful non-invasive procedure to assess compliance during the clinical use of products containing either ISDN or 5-ISMN: it may also be helpful in assessing the clinical pharmacokinetics of 5-ISMN. Less satisfactory correlations were obtained for ISDN (r = 0.84) and 2-ISMN (r = 0.83).

Adult↗
PubMed1984

The influence of food and repeated dosing on the bioavailability of indomethacin from a multiple-units controlled-release formulation.

A concomitant meal did not affect the extent of bioavailability of indomethacin from a multiple-units controlled-release capsule formulation containing enteric-coated pellets, but the presence of food delayed absorption. When a capsule containing 75 mg indomethacin was administered after a 12 h fast, the mean peak drug concentrations in plasma of 2.7 micrograms/ml +/- 0.8 SD occurred at a mean time of 4.2 h (range 2-6 h). When this dose was administered with a substantial breakfast, the mean of the peak plasma concentration of 2.2 micrograms/ml +/- 1.0 SD occurred at 6.4 h (range 5-12 h). Secondary peak plasma drug concentrations, occurring at approximately 14 h after dosing, were more prominent and the times to reach the second peak more variable when the capsules were administered with food. Drug bioavailability after co-administration with food was 91% of that following administration after fasting. When the controlled-release capsule was administered during 3 days in a b.i.d. dosage regimen, drug bioavailability was 103% of that from a standard capsule administered q.i.d. The mean peak level after administration of the last dose of 50 mg as controlled-release capsules was 2.5 micrograms/ml +/- 1.1 SD and the means of peak levels after the penultimate and last doses of 25 mg as standard capsules were 2.0 micrograms/ml +/- 0.3 SD and 2.1 micrograms/ml +/- 0.7 SD, respectively. The controlled-release capsule formulation was a reliable and reproducible source of indomethacin when administered as repeated doses or with food.

Adult↗
PubMed1984

Metabolic fact of 14C-isosorbide 5-mononitrate in humans.

Single oral doses of 20 mg of the carbon-14 labelled form of the antianginal drug isosorbide 5-mononitrate (5-ISMN, Elantan) were essentially completely absorbed and excreted fairly rapidly in the urine. Means of 24, 52, 78, 93 and 96% dose were excreted during 6, 12, 24, 48 and 120 h, respectively. Concentrations of 14C reached peak levels at about 1-2 h when about 86% of the 14C was associated with the parent drug, 5-ISMN (peak mean level 430 ng/ml), and the remainder mainly with the pharmacologically-inactive denitrated product isosorbide. Because the plasma (and urinary) half-life of isosorbide was longer (about 8-9 h) than that of 5-ISMN (about 4.5 h), the proportions of the former in plasma increased relative to the latter. Concentrations of 14C in whole-blood and plasma were similar, implying that 5-ISMN diffused into blood cells. Concentrations of 5-ISMN in saliva and plasma were almost identical, presumably because of the almost negligible plasma protein binding of the drug (less than 5%). At least five metabolites of 5-ISMN were detected in urine - these were isosorbide (about 37% dose), conjugated material (about 25% dose) presumably mainly 5-ISMN-glucuronide, sorbitol (about 7% dose), the parent drug 5-ISMN (about 2% dose) and two unidentified metabolites (about 7 and 4% dose, respectively). The conjugated material was excreted in the urine relatively more rapidly than the denitrated product, isosorbide.

Adult↗
PubMed1984

[Bioavailability of isosorbide-5-mononitrate from delayed-action formulations].

The relative bioavailability of isosorbide-5-mononitrate (IS-5-MN) has been determined after a 3-day period of dosing with 20 mg in standard-release reference tablets and sustained-release capsules at 12-h intervals, 40 mg in sustained-release capsules (Olicard 40 retard) at 24-h intervals and after single oral dose of 60 mg sustained-release capsules (Olicard 60 retard), in a cross-over study with 12 human subjects. Accumulation factors of 1.1-fold or 1.2-fold occurred during administration of 20 mg in standard- or sustained-release tablets and capsules respectively at 12-h intervals, and negligible accumulation of drug occurred after administration of 40 mg in sustained-release capsules at 24-h intervals or was calculated by the superposition principle to occur after doses of 60 mg in sustained-release capsules at 24-h intervals. The mean extent of bioavailability of IS-5-MN from the 20 mg, 40 mg and 60 mg sustained-release capsules was 79%, 67% and 70% respectively, of that from the standard-release reference tablets. The posterior probability that the bioavailability of IS-5-MN was included within the limits 60%-90% of the reference tablets was 97%, 86% and 95% for the 20 mg, 40 mg and 60 mg sustained-release capsules respectively. Means of peak plasma levels of IS-5-MN after administration of the sustained-released capsules were linearly related to the doses administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1983

Determination of heptaminol in human plasma and urine by high-performance liquid chromatography.

Heptaminol was measured in plasma and urine following pre-column derivatisation with o-phthalaldehyde and reversed-phase high-performance liquid chromatography employing fluorescence detection. The limits of detection were sufficient for pharmacokinetic studies of the drug after clinically-used doses. Plasma concentrations of heptaminol reached peak levels (2.19 micrograms/ml) at 0.75 h after single oral doses (0.47 g of heptaminol) and declined with a half-life of 2.1 h (+/- 0.5 S.D.). Heptaminol was well absorbed and excreted rapidly, mainly unchanged in urine, 82% dose (+/- 10 S.D.).

Amino Alcohols↗
PubMed1983

The percutaneous absorption and excretion of promestriene (3-propoxy-17 beta-methoxy-1,3,5(10)-estratriene) in rats and humans.

The percutaneous absorption of 3H-promestriene (an antiseborrhoeic agent; 3-propoxy-17 beta-methoxy-1,3,5(10)-estratriene) was studied in rats and human subjects. Extensive and continual absorption of the tritium label (about 50% dose in 3 days) occurred in rats when the treated area of skin (ca. 30 micrograms/cm2) was occluded; when unabsorbed material was washed off after 6 h, a substantial proportion of the applied 3H (about 25% dose) had been absorbed to be excreted later. In contrast, less than 1% of the 3H applied to the skin of human volunteers (0.1-0.5 mg/cm2) was absorbed within 6 h and subsequently excreted. In rats, tissue concentrations of 3H were greatest in the liver, adrenals and ovaries.

Absorption↗
PubMed1983

The metabolic fate of the anti-androgenic agent, oxendolone, in man.

After intramuscular administration of 16 beta-ethyl-17 beta-hydroxy-4-4-[4-14C]estren-3-one (14C-oxendolone; 300 mg) to 3 human subjects, excretion of 14C was very slow and incomplete despite a 20-day sample collection period. During this time, means of 37% and 21% of the administered 14C were recovered in urine and faeces, respectively, and if excretion continued at the same rate, approximately 90% of the administered 14C would have been excreted during 5-12 weeks. Peak plasma 14C concentrations were reached at 3-6 days after dosing, when they represented 0.2-1.1 micrograms equiv./ml, and declined very slowly thereafter with a half-life of 5.0-6.6 days. Concentrations of unconjugated drug-related steroids circulating in plasma never exceeded about 0.1 microgram/ml. Mass spectroscopic analysis of isolated urinary and faecal metabolites indicated that the principal routes of biotransformation of oxendolone in man are similar to those of the endogenous androgens-namely, reduction of the 4,5-double bond, further reduction of the saturated 3-ketone to the 3 alpha-hydroxysteroid, and oxidation of the 17 beta-alcohol to the corresponding ketone, followed by conjugation, mainly with glucuronic acid, and excretion in the urine and bile.

Adult↗
PubMed1983

Absorption and elimination of a branched-chain alkylpolyethoxylate surfactant in rats.

Oral doses (100 mg/kg/day) of a 14C-labelled branched-chain alkylpolyethoxylate [( C5H11]2CH14CH2O[CH2CH2O]6H; abbreviated [14C]A12E6) were extensively absorbed from the gastrointestinal tract of rats. During a multiple dosing regime, a proportion of 14C equivalent to one daily dose was excreted each day. This 14C was excreted in urine and faeces in equal proportions; less than 1% of the dose was expired as 14CO2. Almost all the faecal 14C came from the bile and had undergone enterohepatic circulation. After cutaneous application of [14C]A12E6 to rats (8 mg, 333 micrograms/cm2) under occluded conditions, about 25% of the dose was absorbed, mainly during the first 12 h. After dosing by both routes, the A12E6 was biotransformed to several metabolites that were more polar than the parent compound. Less than 15% of the dose was excreted unchanged.

Absorption↗
PubMed1983

The metabolism of salicylidene benzylamine, a pro-drug for salicylate, in rats and dogs.

1. Oral doses of [14C]salicylidene benzylamine were well absorbed by rats and dogs and excreted mainly in the urine (92% dose by rat in 24 h and 84% by dog in 48 h). 2. After 50, 100 and 300 mg/kg oral doses to rats, peak mean plasma 14C concn. (mainly salicylic acid) of 77, 243 and 396 micrograms equiv./ml respectively were reached between 2 and 4 h and maintained at this level until about 7.5 h. 14C was cleared more rapidly from the plasma of male rats than from that of female rats. After 44, 85 and 300 mg/kg oral doses to dogs, peak mean plasma 14C concn. (mainly salicylic acid) of 114, 194 and 320 micrograms equiv./ml respectively were reached at 4 h and then declined with a half-life of 6-7 h. 3. Tissue 14C concn. in both species were greatest at the times of peak plasma 14C concn., but in general were lower than those in the corresponding plasma. 4. The major components in rat and dog urine were salicyl alcohol, salicylic acid and salicyluric acid, the first two being excreted partly as glucuronic acid/sulphate conjugates. After initial hydrolysis of salicylidene benzylamine to salicylaldehyde, approximately equal amounts were reduced and oxidized to the corresponding alcohol and acid respectively.

Animals↗
PubMed1983

The metabolism of the anti-inflammatory drug eterylate in rat, dog and man.

Oral doses of 14C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal 14C was probably derived in part, from biliary-excreted material. Peak plasma 14C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicyclate concn. reached a peak (10.9 and 19.8 micrograms/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 micrograms/ml, respectively) and declined with a half-life of about one hour. Tissue concn. of 14C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concn. were lower than those in the corresponding plasma. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major 14C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the 14C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.

Acetanilides↗