The studies were performed in healthy male rats and in one male dog after oral and intravenous administration of [2-carbamoyl-14C]HOE 077. HOE 077 wa rapidly and completely absorbed after oral administration. In blood, tmax was at about 0.5 h and cmax 2.63 +/- 0.92 micrograms equivalents/g in rats (5 mg/kg), and 18.1 micrograms equivalents/g in the dog (15 mg/kg). The predominant half-lives for total radioactivity were in the range of 1 h in the rats and 2 h in the dog, independent of the route of administration. The radioactivity was distributed throughout the body. The highest concentrations were detected in kidneys and liver. Urine (75% of dose) was the main route of excretion after oral and intravenous administration. The radioactivity was almost entirely eliminated 2 days after administration. The compound was intensively metabolized by rat and dog. While the parent compound was the major component in plasma at early time after dosage, more than ten metabolites, accompanied by only small amounts of original substance, were detected in the urine of the first study day. In faeces only metabolites were found. The known metabolites are assumed to be formed by oxidative degradation of the alkylic side chains of the molecule, preferably that in the 2-position of the pyridine ring. The main metabolite in the dog urine was a 2-hydroxyethyl derivative (M4), and in the rat a hippuric acid analogue of HOE 077 (M6). The pyridine carboxylic acid in 2-position of the side chain of HOE 077 (M2) was the predominant metabolite in faeces of rat and dog. In both animal species, more than 80% of the administered radioactivity had been identified. In rats with liver damage caused by treatment with CCl4 the amount of parent compound increased and the rates of formation of metabolites were lower than in normal rats. This can be interpreted as a consequence of the diminished number of hepatocytes able to metabolize HOE 077.

The distribution of 14C-labelled erythromycin following intravenous administration to the guinea pig has been studied by whole body autoradiographic technique. Erythromycin was quickly and extensively distributed throughout the body although penetration into some compartments like brain, spinal cord or vitreous body was limited. High radioactivity concentrations were detected in kidney, liver, lung, upper respiratory tract and in bone marrow. Lung tissue and bone marrow were characterized by delayed elimination of erythromycin. The prenetration of erythromycin into skin could be shown. 24 h after the administration of erythromycin still high amounts of radioactivity were detected in the faeces.

Studies on absorption and distribution in both skin and organism, as well as on elimination and biotransformation were performed in rats, pigs, and rabbits following topical application of the corticoid prednisolone-17-ethyl carbonate-21-propionate (prednicarbate; test name: Hoe 777), which had been labeled with 14C in position 4 for this purpose. After allowing the 0.25% greasy ointment to take effect for 6 hours, about half of the dose applied to rats and three quarters of that applied to pigs could be removed from the application area (rejection rate). Measurable blood levels, which could only be continuously determined in rats, initially occurred 0.5 to three hours after application; they remained very low throughout the experiment and finally reached concentrations between 0.007 and 0.012 micrograms equivalents of prednicarbate per ml 24 hours after administration. The excretion rate was 5 to 6% of the dose applied to rats and maximally 1.9% in pigs. In rats, the absorption after dermal application on an average amounted to 14% in healthy skin and to 22% in abraded skin. In pigs, we received values of about 1% and 4%, respectively. Allowing for species-related differences, the low quantity of absorption was also proved in healthy skin of rats and rabbits by means of in vitro-studies. Thus the amount which had penetrated within 6 hours was 3.3% in the model of the isolated perfused rabbit ear and 0.3% in the penetration chamber model in rats. As adhesive tape strippings and histoautoradiographic studies revealed, the radioactivity was highest in the uppermost layers of the stratum corneum and fell with increasing depth of skin. Our studies demonstrated that the horny layer serves both as a reservoir and as a barrier for prednicarbate. Experimental impairment of the barrier function resulted in an increased amount of active substance penetrating through the skin. During its passage through the organism, prednicarbate is almost completely metabolized, its metabolic fate resembling largely the biotransformation pathway of prednisolone. Among the numerous biotransformation products (about 20-30), 20 beta F-20-dihydroprednisolone and 6 beta-hydroxy-20 beta F-20-dihydroprednisolone were identified as the quantitatively most important metabolites in rats. On the basis of our results, we assume that at the site of action - the skin - highly potent prednicarbate becomes more and more changed by biotransformation on its way into the organism; this process results in formation of numerous metabolites, probably accounting for the very low systemic effect of the compound.

AbstractUnter Anwendung radiometrischer Methoden wurde an Polypropylen‐Prüfkörpern mit 14C‐markierten Präparaten die Migration mehrkerniger phenolischer Antioxidantien wie z. B. Hostanox 03 in flüssige, schmelzbare und feste Lebensmittel geprüft. Die Synthese der 14C‐markierten Antioxidantien aus Bariumcarbonat‐14C erfolgte im Mikromaßstab; die Polypropylenprüfkörper wurden im Technikumsmaßstab an einer Spritzgußmaschine hergestellt. Die Migrationsversuche wurden in der Regel bei 23°C und 49°C, zum Teil auch bei 4°C ausgeführt. Flüßssige und schmelzbare Lebensmittel wie Milch und Margarine wurden in geeigneten Glasgefäßen bei zweiseitigem Kontakt von Prüfkörper und Lebensmittel getestet. Für feste Lebensmittel wie Wurst, Käse und Speck wurde ein Verfahren entwickelt, bei dem Lebensmittelscheiben zwischen zwei Prüfkörpern in Kunststoffbeuteln unter Anlegen von Vakuum fixiert und gelagert wurden. Die nach diesen Methoden radiometrisch bestimmten Migrationswerte für echte Lebensmittel wurden mit den Werten für Lebensmittelsimulantien verglichen. Es zeigte sich, daß mit Hostanox 03 für den Übergang aus Polypropylen in Lebensmittel und Lebensmittelsimulantien vergleichsweise sehr niedrige Migrationswerte erzielt wurden. Bei einer Nachweisgrenze von ca. 0.0002 mg/dm2 waren die Messungen auch im unteren Migrationsbereich mit ausreichender Genauigkeit auszuführen.

After intramuscular injection of ca. 3.5 mg kg-1 diminazene diaceturate-(bis-phenyl-U-14C) to two healthy male calves weighing 185 and 180 kg, levels of radioactivity were determined in blood, plasma, urine, faeces, and in edible tissues. The maximal blood level of 4.6 micrograms and 4.7 micrograms equivalents of diminazene diaceturate ml-1 (calculated from total radioactivity) occurred 15 min (calf C1) and 45 min (calf C2) after administration. The decrease in concentration followed a biphasic process with half lives of 2 and 188 hours. Seven days after treatment 47.1% of the dose had been excreted in the urine and 7.1% in the faeces. The respective values were 72.2% and 10.3% after 20 days. The half lives were similar to those in blood. The main product in urine was unchanged diminazene. Distribution studies showed concentrations which were low in general in edible tissues, i.e. in skeletal musculature and fat (below 1 microgram equivalent g-1), but higher in organs with excretory functions. There were 75.5 micrograms equivalents g-1, corresponding to 22% of the dose, in the liver 7 days after injection. This had decreased to 24.4 micrograms equivalents g-1, corresponding to 15% of the dose, at day 20. Only unchanged deminazene was detected in the liver extracts by thin-layer chromatography. Relay-bioavailability studies showed that the total liver residues were only partially available (mean = 23% of the dose) when fed to rats.

After oral administration, 2 mg/kg in rat and dog, 10 mg in man, of the carbon-14-labeled angiotensin I converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498), absorption (rat 56%, dog 43%, man 56%) occurred rapidly and induced maximum blood levels between 0.25 and 1 h. The radioactivity disappeared from the blood in one or two phases with half-lives of 0.6 h in the rat, 1/3.8 h in dog and 0.5/2.9 h in man. Studies in rats have shown that the radioactivity is distributed rapidly to all tissues. Markedly higher concentrations than in the blood were found in the liver, kidneys, and particularly in the lungs. The elimination from the lungs, which showed the highest concentrations until 5 d after administration, occurred with a half-life of 63 h. In rats, 26% of the dose was excreted with the urine and 71% with the feces. About one third of the dose was eliminated with the bile and about 13% was reabsorbed from the bile. The excretion in the breast milk of rats was low. Placental transfer in pregnant rats was low and transient. The radioactivity recovered from the urine of dogs amounted to 15%, that recovered from the feces amounted to 79%. In man, 56% of the radioactivity was excreted with the urine and less than 40% with the feces. Whereas in rat urine one metabolite dominates, the metabolite patterns in urine and serum/plasma of man and dog - which are very much alike - reveal a different biotransformation with three main metabolites. Unchanged Hoe 498, as well as its dicarboxylic acid and other metabolites appear only in low concentrations in this pattern.

1. Following the dermal application of the carbon-14 labelled broad spectrum antimycotic 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt (ciclopiroxolamine, Hoe 296, Batrafen) in the form of a 1% aqueous cream to healthy human dorsal skin (penetration time: 6 h; occlusive dressing for 5 h), percutaneous absorption accounted on average for 1.3% of the dose applied. Excretion occurred via the kidney, with biological half-lives of 1.7 h. As can be seen from penetration studies of cadaverous skin, the horny layer contained the highest concentrations, with values of 2300-4500 microgram/cm3. The levels determined in the corium were still above the minimum inhibitory concentrations. These concentrations were already obtained at the first test stage (1.5 h after application) and did not change virtually at all over the longer penetration period. According to studies using histoautoradiography, ciclopirox can penetrate the skin via the epidermis and the hair follicles. When ciclopirox-14C-olamine aqueous cream was spread on the surface of fingernails, the radioactive-labelled compound penetrated right through the nail. The percutaneous absorption in dogs was higher, at 5-15% of the dose, than it was in humans. 2. After vaginal application (1 mg/kg) of ciclopirox-14C-olamine in the form of a 1% aqueous cream to bitches, between 42 and 97% of the dose (depending on the animal) was recovered in the urine and faeces, the remainder having penetrated into the tampon used to close the vagina. 3. Ciclopirox is excreted by dogs and man in the urine, primarily as a glucuronide. In humans another glucuronide with properties similar to those of the original substance was detected. Two conjugated, relatively non-polar metabolites were also present in small amounts. The metabolite patterns after oral and dermal application were similar. The binding of ciclopirox to serum proteins in humans was 96 +/- 2% in a concentration range of 0.01-11.0 microgram/ml. 4. Placental transfer was low in the rats studied. Though there was good absorption by the mother animal, the radioactivity in the foetal tissues was always lower than that of the maternal blood.

1 Propyphenazone 220 mg was administered orally to volunteers. Maximum plasma concentrations between 1.5 microgram/ml and 3.5 micrograms/ml were found 30 min later. After comparable doses plasma concentrations in dog and rabbit were lower. The distribution volumes were 2 l/kg. 2 The major metabolic route of propyphenazone is demethylation. The main urinary metabolite is the enolglucuronide of N-(2)-demethylpropyphenazone. 3 Aminopyrine is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations of 10 microgram/ml are reached 1.5 h after a 500 mg dose. The biological half-life is 2-3 h, the relative distribution volume 60% on average, and binding to plasma proteins approximately 15%. 4 Unchanged aminopyrine is only excreted in small quantities. The major routes of metabolism are demethylation (4-methylaminoantipyrine and 4-aminoantipyrine) and acylation (4-acetyl and 4-formylaminoantipyrine). There are other biotransformation products. 5 After oral administration of [14C]-dipyrone 480 mg the maximum serum concentration of 13.4 +/- 0.8 microgram/ml occurred at 1-1.5 hours. 6 Dipyrone was not detectable in serum or urine. Four of seven metabolites were identified, and were identical with the main metabolites of aminopyrine.

British Journal of Clinical PharmacologyVolume 7, Issue S1 p. 41S-50S Free Access Kinetics and metabolism of clobazam in animals and man. M Volz, M VolzSearch for more papers by this authorO Christ, O ChristSearch for more papers by this authorHM Kellner, HM KellnerSearch for more papers by this authorH Kuch, H KuchSearch for more papers by this authorHW Fehlhaber, HW FehlhaberSearch for more papers by this authorD Gantz, D GantzSearch for more papers by this authorP Hajdu, P HajduSearch for more papers by this authorF Cavagna, F CavagnaSearch for more papers by this author M Volz, M VolzSearch for more papers by this authorO Christ, O ChristSearch for more papers by this authorHM Kellner, HM KellnerSearch for more papers by this authorH Kuch, H KuchSearch for more papers by this authorHW Fehlhaber, HW FehlhaberSearch for more papers by this authorD Gantz, D GantzSearch for more papers by this authorP Hajdu, P HajduSearch for more papers by this authorF Cavagna, F CavagnaSearch for more papers by this author First published: February 1979 https://doi.org/10.1111/j.1365-2125.1979.tb04664.xCitations: 67AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References ALTON, K.B., GRIMES, R.M., SHAW, C., PATRICK, J.E. & McGUIRE, J.L. (1975). Biotransformation of a 1, 5 benzodiazepine, triflubazam, by man. Am. Soc. Pharmac. exp. Ther., 3, 352– 360. GRIMES, R.M., ALTON, K.B. & SHAW, C. (1973). Metabolism of a 1, 5 benzodiazepine, ORF 8063, in man. Pharmacologist, 15, 254. JOMMI, G., MANITTO, P. & SILANOS, M.A. (1964). Metabolism of diazepam in rabbits. Arch. Biochem. Biophys., 108, 334– 340. OESCH, F. (1973). Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica, 3, 305– 340. ROSSI, S., PIROLA, O. & MAGGI, R. (1969). Sintesi di 1,2,4,5-tetraidro-2,4-dicheto-3H-1, 5 benzodiazepine. La Chimica e l'Industria, 51, 479. RUPP, W., BADIAN, M., CHRIST, O., HAJDU, P., KULKARNI, R.D., TAEUBER, K., UIHLEIN, M., BENDER, R. & VANDERBEKE, O. (1978). Pharmacokinetics of single and multiple doses of clobazam in humans. Br. J. clin. Pharmac., 7, 51S– 57S. SCHOLTAN, W. (1962). Über die Bindung der Langzeitsulfonamide an die Serum-eiweisskörper. Makromolekulare Chemie, 54, 24– 58. SCHWARTZ, M.A., BOMMER, P. & VANE, F.M. (1967). Diazepam metabolites in the rat: Characterization by high resolution mass spectrometry and nuclear magnetic resonance. Arch. Biochem. & Biophys., 121, 508– 516. SCHWARTZ, M.A., KOECHLIN, B.A., POSTMA, E., PALMER, S. & KROL, G. (1965). Metabolism of diazepam in rat, dog and man. J. Pharmac. exp. Ther., 149, 423– 435. DE SILVA, J.A.F., SCHWARTZ, M.A., STEFANOVIC, V., KAPLAN, J. & D'ARCONTE, L. (1964). The determination of diazepam (Valium) in blood by gas liquid chromatography. Analyt. Chem., 36, 2099. ULLBERG, S. (1954). Techniques used in the autoradiographic work. Acta Radiologica. Stockholm, 118, 22– 31. Citing Literature Volume7, IssueS1February 1979Pages 41S-50S ReferencesRelatedInformation

British Journal of Clinical PharmacologyVolume 4, Issue S2 p. 109S-116S Free Access Kinetics and metabolism of nomifensine in animals. HM Kellner, HM KellnerSearch for more papers by this authorC. Baeder, C. BaederSearch for more papers by this authorO. Christ, O. ChristSearch for more papers by this authorW. Heptner, W. HeptnerSearch for more papers by this authorI. Hornke, I. HornkeSearch for more papers by this authorRM Ings, RM IngsSearch for more papers by this author HM Kellner, HM KellnerSearch for more papers by this authorC. Baeder, C. BaederSearch for more papers by this authorO. Christ, O. ChristSearch for more papers by this authorW. Heptner, W. HeptnerSearch for more papers by this authorI. Hornke, I. HornkeSearch for more papers by this authorRM Ings, RM IngsSearch for more papers by this author First published: April 1977 https://doi.org/10.1111/j.1365-2125.1977.tb05736.xCitations: 25AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References CHRIST, O., GLEIXNER, K., KELLNER, H-M., MÜLLER, R. & RUPP, W., (1972). Pharmakokinetische Untersuchungen nach oraler Verabreichung von 3, 7-Dimethyl-l-(5-oxo-hexyl)-xanthin-14C (BL 191 -14C) an Ratten, Hunde und Menschen. Arzneimittel.-Forsch. (Drug Res.) 22, 1933–1937. HEPTNER, W., HORNKE, I., CAVAGNA, F., FELHABER, H-W., RUPP, W., NEUBAUER, H.P. (1977). Metabolism of nomifensin in man and animal species. Arzneimittel.-Forsch. (Drug Res.) (inpress). HOFFMANN, I., EHRHART, G. & SCHMITT, K. (1971). 8-amino-4-phenyl-1,2,3,4-tetrahydroisochinolin, eine neue Gruppe antidepressiver Psychopharmaka. Arzneimittel.-Forsch. (Drug Res.) 1, 1045. HOFFMANN, I., (1973). 8-amino-4-phenyl-1,2,3,4-tetrahydroisochinoline, a new antidepressant. Arzneimittel.-Forsch. (Drug Res.) 23, 45–50. KELLNER, H.M., CHRIST, O., RUPP, W., HEPTNER, W. (1969). Resorption, Verteilung und Ausscheidung nach Gabe von 14C-markiertem HB 419 an Kaninchen, Ratten und Hunde. Arzneimittel.-Forsch. (Drug Res.) 19, 1388–1400. KLOSS, G., KELLNER, H.M., KÖTTER, CH. (1973). Vakuum-Kontakt-Methode bei der Makroauto-radiographie. Z. Naturforsch. 28e, 468. RISING, P., ILLING, H.P.A., JOHNSON, P. & YEOMANS, M.A. (1977). The metabolism of a substituted aminoacetamido benzophene and cyclisation to the corresponding benzodiazepine in rat in vivo. Xenobiotica (in press). SCHOLTAN, W. (1962). Über die Bindung der Langzeitsulfonamide an die Serumeiweisskorper. Makromolec, Chemie 54, 24. ULLBERG, S. (1954). Technique used in Autoradiographic work. Acta radiol. Stockh. 118, 22–31. Citing Literature Volume4, IssueS2April 1977Pages 109S-116S ReferencesRelatedInformation

The aim of this study was to investigate the influence of glibenclamide on insulin release via insulinotropic gut factors and via a direct action on the pancreas. Maximum peripheral IRI levels appeared 1 minute after intragastric administration of the minimal effective dose of glibenclamide to rats. The corresponding drug levels were high (600 ng/g) in the duodenal mucosa, but low (2 ng/ml) in the peripheral serum. These concentrations were too low to cause insulin release by direct action on the pancreas. Intragastric glibenclamide increased the amount of “duodenal insulin releasing activity” (DIRA) in the mucosa immediately after drug administration. When glibenclamide was dissolved in plasma at a high concentration (1 μg/ml) and then injected into the coeliac trunk of an in-situ rat pancreas preparation, no additional effect on portal IRI levels was measured as compared with injection of serum alone. In contrast significant IRI release was noticed when glibenclamide was dissolved in serum (1 μg/ml) of rats pretreated with the drug intragastrically. The plasma of pretreated rats without addition of glibenclamide was ineffective. The results suggest that glibenclamide may have two effects, one releasing insulin at the pancreas directly, and the other inducing the release of a gastrointestinal factor which amplifies the first effect. Neither glibenclamide nor the factor alone can provoke an IRI release under physiological conditions. The possible importance of these findings for the regulation of insulin secretion is discussed.

Fenbendazol wirkt bei einer Dosis von 5 bis 10 mg/kg p.o. auf alle bedeutenden Magen-, Darm-Nematoden inkl. einiger Organnematoden von Schwein, Schaf, Rind und Pferd, wobei nicht nur die Adulten, sondern auch die chemotherapeutisch schwer zu beeinflussenden Entwicklungsstadien (O. ostertagi) praktisch vollständig eliminiert werden. Bei extrem guter Verträglichkeit (bis zu 1000fach therapeutischer Dosis) und fehlender teratogener Wirkung konnte hier ein vielversprechendes Anthelminthikum entwickelt werden.