[Pharmacokinetics and biotransformation following topical use of the local corticoid prednicarbate]. / Untersuchungen zur Pharmakokinetik und zur Biotransformation nach topischer Anwendung des lokalen Kortikoids Prednicarbat.

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.

Kinetics and metabolism of nomifensine.

Metabolic and pharmacokinetic studies of nomifensine maleate, a tetrahydroisoquinoline derivative with antidepressant properties, are reviewed. Results of pharmacokinetic studies indicate that nomifensine has a short distribution phase and a large volume of distribution. It is rapidly metabolized to its N-glucuronide. Plasma levels of nomifensine-N-glucuronide are up to 100-fold higher than those of nomifensine, obviously because of a smaller volume of distribution. As nomifensine-N-glucuronide is extremely unstable and cleaved to nomifensine, determinations of nomifensine are easily falsified. It is therefore recommended only to determine the sum of nomifensine and its N-glucuronide (total nomifensine) in clinical trials. Kinetics of total nomifensine can best be described by the open two-compartment model: Maximum plasma levels are obtained 1-2 hours postadministration; mean elimination half-life is 2 hours. Excretion is almost entirely by the kidneys, with approximately 88% of an oral dose excreted within 24 hours.

[Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topical and systemic administration]. / Untersuchungen zur Pharmakokinetik und Biotransformation des Antimykotikums Ciclopiroxolamin bei Tieren und beim Menschen nach topischer und systemischer Anwendung.

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.

Metabolism of nomifensine (Alival, Merital): isolation and identification of the conjugates of nomifensine-14C from human urine.

1 It can be stated in regard to the metabolism of nomifensine that the metabolites and also the starting compound are present in alkaline urine almost completely in conjugated form. 2 The metabolites M I-M III represent about 30% of the radioactivity excreted with urine. Two-thirds are N-glucuronides and one-third O-glucuronides. 3 Nearly the entire remainder of the renally eliminated radioactivity in nomifensine which is present in conjugated form as N-glucuronide. 4 Thus over 90% of the metabolites formed in man and excreted via urine have been identified.