Hans Wendt

Investigations of pharmacokinetics of ethinyloestradiol to specific consideration of a possible first-pass effect in women

Ethinyloestradiol-3H was given intravenously and orally to four and three women, respectively, in a dose of 60 micrograms and 3 mg. To another three female volunteers, 100 micrograms of ethinyloestradiol was administered by both routes in succession. Drug concentration in plasma and total radioactivity in plasma, urine and faeces were measured for different periods of time. Intraindividual comparison of the area under the drug level vs. time curve after intravenous and oral administration of 100 micrograms showed that ethinyloestradiol is subject to an about 60% first-pass effect in women. The time course of ethinyloestradiol concentration in plasma can be described by a 3-compartment model after intravenous injection and by a 2-compartment model after oral administration, because an early disposition phase with a half-life of about 15 minutes only becomes visible after i.v. injection. On an average, the terminal half-life of unchanged ethinyloestradiol level and total radioactivity was calculated to be about 1 day. However, a high variability was found with this parameter as well as with the rate and degree of elimination in urine.

Kinetics and biotransformation of lormetazepam

A specific and sensitive radioimmunoassay has been developed for a new benzodiazepine, lormetazepam. After intravenous injection, lormetazepam levels in plasma fell in three (α, β, γ) dispositional phases, two of them (α, β) mainly reflecting different distribution processes. The terminal (γ) phase correlated well with the rate of renal elimination of glucuronides. Oral doses were completely absorbed with widely varying absorption half‐lifes (t½s) amounting to an average of 0.67 ± 0.53 hr. Dose‐dependent maximum plasma levels were reached in about 2 hr. Lormetazepam undergoes first‐pass metabolism of about 20% of an oral dose. Total clearance was in the range of 200 ml/min. There was a trend toward slower terminal disposition phase in elderly subjects. In younger subjects, the terminal phase t½ was about 10 hr. Lormetazepam glucuronide peak plasma levels were reached by about 6 hr. Thereafter, the level fell in one (elimination) phase, with a t½ of 12 hr in young subjects and with a significantly (p < 0.05) different t½ of about 20 hr in the elderly. Renal clearance was calculated as about 30 to 40 ml and did not show an age‐dependent difference. Recovery of lormetazepam glucuronide with urine amounted to 70% to 80% of the dose during 72 hr after intravenous injection in both age groups.

The pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans. I. Absorption, distribution, elimination and metabolism of lormetazepam-5-14C.

SummaryThe pharmacokinetics and metabolism of the new benzodiazepine lormetazepam were investigated in five male volunteers using thel4C-abelled drug (position 5). Lormetazepam was administered intravenously and orally, at a dose of 0.2 and 2 mg respectively, to each of the test subjects.Measurements of total radioactivity showed that the drug was absorbed completely and eliminated almost exclusively by the renal route. Maximum plasma level of active ingredient and total radioactivity were observed about 2 hours and 5 hours following oral administration. As early as 30 min following oral administration, concentration of active ingredient amounted to 80% of the maximum values. After both treatments the terminal half-life of total radioactivity and lormetazepam glucuronide in plasma corresponded to the half-life of elimination in urine of about 13 hours.After enzymatic hydrolysis with β-glucuronidase/arylsulphatase, an average of 90% of total radioactivity from various urine and plasma samples was extractable with ether. Extracts from plasma contained only unchanged drug, indicating free and conjugated lormetazepam as ingredients of total radioactivity. Extracts from urine could be separated into lormetazepam and its N-demethylation derivative lorazepam. The relative amount of excreted lorazepam conjugate was demonstrated to be time-dependent, probably due to enterohepatic circulation. Since less than 6% of the total dose was demethylated by both routes of administration, it can be assumed that lormetazepam is the active product.

DEVELOPMENT AND APPLICATION OF A RADIOIMMUNOASSAY OF THE NEW PROGESTAGEN GESTODENE

A radioimmunoassay for the determination of gestodene (17-ethinyl-13-ethyl-17 beta-hydroxy-4,15-gonadien-3-one) in human plasma is described with regard to procedure, specificity, accuracy and reproducibility. Antiserum was raised against gestodene-3-O-(carboxymethyl)oxime-BSA in rabbits and [9,11-3H]-gestodene tracer was used with a specific radioactivity of 2.16 TBq/mmol. The final antiserum dilution was 1: 200,000. RIA was performed according to routine methods using diethylether plasma extracts and the charcoal separation technique. Cross-reactivity of antiserum with cortisol, 17 beta-estradiol, progesterone, testosterone and ethinylestradiol was less than 0.03%; levonorgestrel exhibited a 5% cross-reactivity. No cross-reactivity with metabolites of gestodene or ethinylestradiol was found. Accuracy and precision of the assay were tested using human plasma samples spiked with 1, 5 and 10 ng/ml gestodene. Accuracy was within 94 to 104% of the nominal values. Within-assay and between-assay coefficients of variation were in the range of 4.7-6.5% and 10.3-13.1%, resp. This RIA was used to follow plasma gestodene levels after single oral administration of 75 micrograms of gestodene combined with 30 micrograms ethinylestradiol as tablet and coated tablet in a cross-over design in 6 female test subjects. Plasma gestodene levels were equivalent after both treatments.

Thermographic analysis of skin test reaction using aga thermovision

SummaryThe course of infrared thermography including isothermograms on the skin surface was investigated considering blood flow, redness of the skin and permeability of blood vessel, in the following skin reactions:1.Intracutaneous injection of histamine and histamine liberator compound 48/80 increased the heat radiation. Local application of antihistamine externa which decreased the development of the urticarial histamine reaction, increased the infrared radiation of the skin surface. Combined injection of histamine or histamine liberators with antihistamines in a sufficient dosis (1:1 respectively 4:1) diminished also the heat radiation in addition to the urticarial reaction.2.The Pyrexal reaction of the skin with early erythema and later papule development shows an equivalent picture in the AGA Thermovision. The pretreatment of the skin with corticosteroid ointments shows a corresponding lowering of the erythema, of papule development as well as of heat radiation. The blanching of corticosteroids after occlusive dressing is difficult to recognize by the isotherms of AGA Thermovision.3.Allergic reactions of the immediate type show, corresponding to the wheal eruption, a marked increased of heat radiation combined with a projection of the enlarged veins on the skin surface.4.Allergic reactions of the delayed type are combined with a definite elevation of heat radiation of the skin. The area of a positive skin test with allergic eczematous reaction shows a distinct elevation of a infrared radiation. Although the allergic skin area which was substantiated by a positive skin test was no longer visible, a distinct infrared radiation could be detected. Preventive treatment of the test area of skin patch-testing with corticosteroids inhibits the heat radiation even if the allergic eczematous reaction occurs faintly. The thermographic analysis of the different skin test reactions complied with the morphological aspects of the reaction.ZusammenfassungDie Infrarotthermographie einschließlich die Darstellung der Isothermogramme auf der Hautoberfläche wurde zur Analyse der Durchblutung, Erythementwicklung und der Gefäßpermeabilität bei den folgenden Hauttesten verwandt.1.Intracutane Injektion von Histamin und des Histaminliberators 48/80: Beide Reaktionen führen zu einer deutlichen Erhöhung der Wärmeabgabe von der Haut. Durch lokale Applikation von Antihistaminen wird die Entwicklung der urticariellen Reaktion vermindert. Gleichzeitig stellt sich die Infrarotstrahlung von der Hautoberfläche stärker dar. Erst bei höherer Dosis von Antihistaminen, die gleichzeitig mit Histamin oder dem Histaminliberator intracutan injiziert wurden, vermindert sich auch die Wärmestrahlung von der Hautoberfläche zugleich mit der Verminderung der urticariellen Reaktion.2.Pyrexal-Resektion der Haut: Unter Entwicklung eines frühzeitigen Erythems und einer sich später entwickelnden Papel zeigt sie ihr äquivalentes Bild in der AGA-Thermovision. Die Vorbehandlung der Haut mit Corticosteroidexterna zeigt eine gleichsinnige Veränderung der Erythembildung, der Papelentwicklung und der Wärmeabstrahlung von der Haut. Die Abblassung der Haut unter dem Okklusivverband mit Corticosteroiden ist kaum mittels der Isothermogramme der AGA-Thermovision darzustellen. Die Abschwächung der Wärmestrahlung von der Hautoberfläche durch Corticosteroide ist dabei empfindlicher als die Minderung der morphologisch erfaßbaren Reaktion.3.Allergische Reaktionen vom Soforttyp: Diese zeigen entsprechend der Quaddeleruption eine deutliche Erhöhung der Wärmestrahlung von der Haut, die mit einer Wärmeprojektion erweiterter Venen sich kombiniert. 24 h nach Ablauf einer solchen Hautreaktion ist die erhöhte Infrarotstrahlung am Orte der Reaktion noch erkennbar.4.Allergische Reaktionen ekzematösen Typs: Diese Reaktion vom verzögerten Typ ist mit einer deutlichen Erhöhung der Wärmestrahlung von der Haut verbunden. Auch bei abgeklungener Testreaktion ist der Ort der positiven epicutanen Läppchenteste durch erhöhte Wärmeabgabe deutlich charakterisiert. Eine vorhergehende Behandlung des Testfeldes mit Corticosteroiden vermindert das Ausmaß der Wärmeabgabe, auch wenn das morphologische Bild der allergischen ekzematösen Kontaktreaktion noch besteht. Die thermographische Analyse der verschiedenen Hautteste ergänzt die morphologische Betrachtungsweise eindrucksvoll.

The pharmacokinetics and biotransformation of14C-Lisuride hydrogen maleate in rhesus monkey and in man

Summary14C-labelled lisuride hydrogen maleate was administered intravenously (25 ug) and orally (200 ug) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 ± 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose.Determination of 1 4C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a halflife of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant.From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose.The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N′-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds atC2/C3 and C9/Ci0.