The relationship between dose, pharmacokinetics, plasma-concentrations and antithrombotic effects of nafazatrom.

Nafazatrom is rapidly and almost completely absorbed after oral administration. However, the plasma levels of unchanged nafazatrom are very low, suggesting an extensive biotransformation during a first passage through the liver. The concentrations of nafazatrom in the plasma therefore, may only reflect indirectly the effective concentration at the receptor site. Concentrations, half-life and distribution of nafazatrom between aqueous and liquid compartments suggest that the cellular membrane may be the site of action.

Pharmacokinetic studies following systemic and topical administration of [14C]bifonazole in man.

[14C]Bifonazole (1-[(4-Biphenylyl)-phenylmethyl]-1H-imidazole, Bay h 4502, Mycospor) was administered systemically (i.v.) and topically (dermally) in different formulations to a total of 17 volunteers. In the serum, the concentrations of total radioactivity and of the unchanged drug were determined by liquid scintillation counting techniques and by thin-layer densitometry, respectively. Urine and feces were collected and radioassayed. The extent of percutaneous absorption was calculated. In addition, distribution of the unchanged drug in the layers of the skin was studied radiometrically in three patients. After intravenous administration, bifonazole was eliminated from the serum largely in metabolized form. The half-lives of elimination of the radioactivity from the serum were approximately 7 and 42 h. Within 5 days 45% of the dose was excreted with the urine, and 39% with the feces. After topical application to healthy skin areas, under occlusive conditions, less than 1% of bifonazole was absorbed percutaneously from a 1% solution or cream, and the amount absorbed was excreted with the urine and the feces in approximately the same proportions as after i.v. administration. Following administration of the drug to inflamed skin, the proportion absorbed was 3 to 4% of the dose administered and thus higher than after application to normal skin. Studies on depth localization showed that the drug has a high capacity for skin penetration. Even in the lower layers of the epidermis, bifonazole was present in amounts several times as high as the minimum inhibitory concentrations for dermatophytes measured in vitro.

Pharmacokinetic fundamentals of vaginal treatment with clotrimazole.

Absorption of clotrimazole after vaginal application was estimated to be between 3 and 10%. In order to investigate the fate of clotrimazole reaching systemic circulation, pharmacokinetic studies following oral and intravenous administration were carried out. The concentrations of clotrimazole in vaginal fluid and in blood plasma after vaginal application of 200 and 500 mg were determined using a specific assay by quantitative thin-layer chromatography. Fungicidal concentrations of clotrimazole in vaginal fluid up to 3 days after application of one vaginal tablet containing 500 mg were found. In contrast, clotrimazole plasma levels were lower than 0.01 micrograms/ml, demonstrating that clotrimazole is rapidly metabolized.

[Pharmacokinetic studies after oral application of radioactively labelled D-penicillamine]. / Pharmakokinetische Untersuchungen nach oraler Applikation von radioaktiv markiertem D-Penicillamin an Probanden

14C-labelled D-penicillamine was given orally to healthy test subjects in different dosages. The time course of serum activity was followed up to 5 weeks and the urinary activity was measured for 4 days. The obtained results equalled the sum of active substance and its 14C-labelled biotransformation products. The maximal serum concentration appeared about 2 hours after ingestion, the obtained concentrations being proportional to the dosis. Thereafter the concentration declined first relatively fast, then increasingly slower. From the 4th day after ingestion the half time of elimination was 8 days. The urinary excretion was dose dependent; the urinary concentration increasing with higher dosage. The later long half time of elimination corresponded to disappearance from the blood of the portion of the drug firmly getting attached to collagen and elastic tissue structures. The several weeks latency of onset of antirheumatic effect may be due to the fact that the portion of the drug getting attached to connective tissue accumulates slowly.

[Pharmacokinetic studies following administration of 14 C-D-penicillamine to rats]. / Pharmakokinetische Untersuchungen nach Applikation von 14C-D-Penicillamin an Ratten.

14C-Labelled D-penicillamine [D-(--)-alpha-amino-beta-mercapto-isovaleric acid; Trolovol] was administered to rats in doses of 10 to 50 mg/kg body weight orally or i.v. A dose of 0.25 mg per rat was used for intra-articular injection (knee joint). 4 h after a single i.v. administration about 30% of the given amount were detected in the animal. This amount of activity was located predominantly in skin and connective tissues and was eliminated very slowly. 2 days after administration 20 (i.v.) or 10 (p.o.)%, resp., of the radioactivity administered were found in the animal, in any case half of it in the skin. In comparison to the skin and the connective tissues, the parenchymatous organs and the central nervous system showed distinctly lower concentrations. The activity is eliminated mainly with the urine: 80 (i.v.) or 50 (p.o.)%, resp., of the administered activity were eliminated renally within 48 h. 90% of it were excreted within 6 (i.v.) or 7 (p.o.) h, resp., after administration. Less than 2 (i.v.) and approx. 40 (p.o.)%, resp., of the given activity were found in the faeces collected for 2 days. The extent of gastrointestinal absorption was about 2/3 of the dose administered. Up to 24 h after the three modes of administration distinctly detectable concentrations were to be located in the lig. patellae of the knee joints, somewhat lower values in the ligaments between the articular cartilages. Studies carried out on rats in parallel with an arthritis experimentally induced (secondary phase, after injection of Freund's adjuvant) demonstrated the same activity distribution compared with the pattern which was obtained on healthy rats.

Pilot trials with a fluorescent whitening agent of the bis(triazoly) stilbene-disulfonic acid type in golden orfes.

Golden orfes were examined for uptake, distribution, and elimination of radioactivity administered in the form of a 14C-labelled fluorescent whitening agent (FWA) of the bis(triazolyl)stilbenedisulfonic acid type. Results of these studies are given below. Pilot trials using FWA concentrations of 10 and 100 ppb and a population density of 1 fish per liter show that an equilibrium between uptake and elimination of the FWA develops in the animals within a period of one week; i.e., the incorporated traces of the FWA are not irreversibly bound. The radioactivity is mainly located in the gall bladder and in the intestinal contents, as well as in the liver, throat, and gills. The muscular system (filet) is virtually free from activity. Approximately 1-2% of the FWA amount administered per animal (corresponding to the concentration factors of 7-14) can be temporarily detected in the fish. Radioactivity is eliminated comparatively quickly. Two days following the transfer of the fish into water free from FWA a concentration factor as low as 1 is reached, i.e. from this time the FWA concentration in the animals decreases to less than 10 resp. 100 ppb.