Biomedical subjects
Publications and source records attributed to L F Chasseaud.
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The bioavailability of rifampicin and isoniazid from formulations containing these drugs in combination has been compared to that from formulations containing either drug alone. No formulation-related differences in either rates or extent of bioavailability were found after administration of each formulation. Mean peak serum concentrations of rifampicin (8.2-11.7 mug/ml) occurring 2 to 4 h after doses of 600 mg, and isoniazid (3.6-4.8 mug/ml) occurring 0.5 to 1 h after doses of 300 mg, were similar to those reported in the literature.
1. An oral dose of the coronary vasodilator 4-(3,4,5-trimethoxy[14C]cinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was well absorbed and more than 60% of the dose was excreted within 24 h. In 5 days, rats, dogs, and man excreted in the urine and faeces respectively 36.7% and 58.3%, 33.4% and 68.6%, and 61.3% and 38.1% dose. Faecal radioactivity was probably excreted via the bile. 2. Plasma concentrations of radioactivity reached a maximum within about 1 h in all three species and declined fairly rapidly (t0.5 less than 3 h). For several hours, more than 50% of the plasma radioactivity was due to unchanged drug. After correction for dose and body weight (normalization), peak plasma concentrations of unchanged drug in man, rat and dog were in the approximate ratio 100 :30:1. 3. Similar metabolites were excreted by the three species, but the relative proportions differed. Rats and man excreted 17.2% and 15.9% respectively as unchanged drug in the urine whereas dogs excreted only 3.6%. Rat bile and urine contained 4.3% and 9.8% dose respectively as glucuronides of the mono-O-demethylated compounds and dog and human urine contained 9.0% and 2.6% respectively of these metabolites. The corresponding pyrrolidone accounted for 2.5%, 5.5% and 5.1% respectively in rat, dog and human urine. Complete O-demethylation also occurred since 4-(3,4,5-trihydroxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was present in rat faeces (22.1% dose).
A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.
1. The absorption and tissue distribution of radioactivity has been studied in rabbits after application of a cream containing 10 mg of the 3H-labelled 1-(2,4-dichloro-beta-[(p-chlorobenzyl)oxy]phenethyl) imidazole nitrate (econazole nitrate, Pevaryl) to the normal or abraded skins of rabbits. 2. Approximately one-third of the dose was absorbed through the occluded normal skins of rabbits during 8 days, mainly during 7 to 24 h. In the same time interval, slightly more of the dose was absorbed through the occluded abraded skins of rabbits at slightly greater rates. Co-formulation of triamcinolone acetonide in the cream reduced and delayed the peak rates of absorption through normal and abraded skin, but the extent of absorption during 8 days was similar in the presence or absence of triamcinolone acetonide. 3. After application to normal skin or abraded skin, the peak of mean concentrations in the plasma of 220 ng/ml (range 132-276 ng/ml) or 307 ng/ml (range 270-321 ng/ml), respectively, occurred at 24 h. Tissue distribution of radioactivity was similar after application to normal or abraded skin, and concentrations were highest in the liver, kidneys and gastrointestinal tract (which are the organs of biotransformation and excretion) and also in the adrenals and to a lesser extent in the uterus, ovaries and untreated skin. 4. After application of a cream containing 5 mg of 3H-econazole nitrate to the vaginas of rabbits, approximately one-third of the dose was absorbed during 8-24 h, and rates of excretion were higher through the more permeable vaginal membrane. 5. After vaginal doses of 5 mg, a peak concentration of 209 ng/ml occurred at 6 h in the plasma. Tissue concentrations of radioactivity after vaginal doses were highest in liver, kidneys, gastrointestinal tract, adrenals and ovaries, and the tissue distribution was similar to that observed after cutaneous doses.
On the basis of plasma concentrations of pantothen[14C]ate, after its intravenous administration, a three compartment open model was proposed to predict the pharmacokinetics of pantothenate in dogs. The model assumed a central compartment comprising the plasma and other extracellular fluids, and distribution into two other peripheral compartments, one of which included the liver. Elimination of unchanged pantothenate was assumed to occur by metabolism from the compartment which included the liver. Distribution of pantothen[14C]ate from the plasma compartment into the liver compartment was shown to be very rapid; during 10 min after intravenous administration about 80 per cent of the dose had been cleared from the plasma compartment. The model successfully predicted the influence (first pass effect) of the liver on the fraction of an oral dose which reached the peripheral plasma unchanged.
The excretion and plasma concentrations of radioactivity and chromatographic patterns of radioactive components in plasma and excreta have been compared in rats, dogs and man after oral doses of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF 178; procetofene; Lipanthyl¿). 2. In rats, 48.1% of a single dose of 25 mg/kg was excreted in the urine, and 48.6% in the faeces. In dogs, 23.1% of a single dose at the same level was excreted in the urine, and 71.8% in the faeces, but 88.1% of a dose of 300 mg to man was excreted in the urine, and only 5.1% in the faeces. Peak levels of radioactivity in the plasma of all three species studied were similar (20--30 mug/ml) after doses at these levels and concentrations declined thereafter with half-lives of 7--24 h in rats and dogs, and 7 h in man. The half-life of radioactivity concentrations in rat plasma was not altered by repeated daily doses for 7 days. 3. Whole-body autoradiography of rats showed that radioactivity was largely associated with the liver, kidneys and gut, which are the organs of biotransformation and excretion, although relatively high levels were present in lungs and blood, and small amounts of radioactivity had a widespread distribution into some peripheral tissues during 2--7 h after dosing. 4. The available chromatographic evidence indicated that the most important biotransformation pathway appeared to be ester hydrolysis to LF 178 acid and formation of water soluble conjugates of this acid. This pathway appeared similar to that of the related drug clofibrate (ethyl p-chlorophenoxyisobutyrate).
Sebaceous gland non-specific esterase activity was suppressed following application to mouse skin of 2 electrophilic alpha beta-unsaturated compounds, o-chlorobenzylidenemalononitrile and beta-nitrostyrene, but not by three others.
An oral dose of 5 mg of 14C-isosorbide dinitrate was rapidly absorbed, biotransformed and excreted by human subjects. Peak whole blood concentrations of radioactivity were reached after 1.5 to 2 hours and declined relatively slowly. The radioactivity in whole blood mainly represented metabolites, isosorbide mononitrates. The peak concentrations found were 4.5, 11.7 and 34.3 ng/ml of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate, respectively, in the blood of one subject and 5.9, 15 and 61.3 ng/ml, respectively, in the blood of another subject. However, concentrations of the metabolites declined relatively slowly during 6 h after the oral urine of the first day (ca. 78%). The results showed that isosorbide mononitrates were available to contribute to the pharmacological action.
1. The percutaneous absorption of a novel oxazolino corticosteroid, 14C-9alpha-fluoro-11beta,21-dihydroxy-3,20-dioxopregna-1,4-dieno[17alpha,16alpha-d]-2'-methyloxazolidine-21-acetate (L 6400) and 3H-triamcinolone acetonide (TA) was compared in rats, pigs and humans after application of a cream formulation to the skin and occlusion. 2. Within 96 h, up to 4.0% of the applied dose of L 6400 (permeability constant Kp 0.28) and up to 8.7% of TA (Kp 0.42) were percutaneously absorbed in rats. 3. Microhistoautoradiography showed that most of the applied radioactivity remained on the skin of rats. Radioactivity in the skin was mainly associated with the epidermis. 4. Within 120 h, up to 1.5% of the applied dose of L 6400 (Kp 0.16) and up to 0.5% of TA (Kp 0.07) were percutaneously absorbed in pigs. Plasma concentrations of radioactivity were maximal 48 h after application of 3H-TA whereas they were undetected after application of 14C-L 6400, because of the relatively lower specific activity of this 14C-steroid. 5. Both corticosteroids were allowed to remain in contact with human skin for 5 h and during that time, up to 1.1% of the applied dose of L 6400 (Kp 0.82) and up to 0.9% of TA (Kp 0.94) were absorbed. Results in four human subjects varied twenty-eightfold for L 6400 and fivefold for TA. Plasma concentrations of radioactivity were undetected after application of L 6400. In one subject treated with 3H-TA they were maximal after 2 h but were undetected in another subject and were found only in early samples from two others. 6. The results suggested that both corticosteroids were poorly absorbed through normal skin in rats, pigs and humans.
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