Twenty two healthy males participated in a randomised, placebo-controlled, double blind, cross-over study to investigate the influence of simvastatin on the pharmacokinetics of ramipril and its active metabolite (ramiprilat), and on the ACE-inhibiting effect of ramiprilat. During two study periods, each of 7 days, subjects received daily either simvastatin 20 mg at 19.00 h or placebo; ramipril (5 mg) was given on Day 5 of each of the periods. Plasma concentrations of ramipril and ramiprilat and ACE-activity were measured in sequential blood specimens, and ramipril and ramiprilat concentrations were measured in urine. Blood and urine collections for pharmacokinetic and pharmacodynamic assessment were made up to 72 h after the dose of ramipril. The mean AUC of ramipril for ramipril+placebo (R+P) and ramipril+simvastatin (R+S) was 22.2 and 21.3 ng.h.ml-1, respectively; for ramiprilat the corresponding figures were 61.3 and 57.6 ng.h.ml-1. The urinary excretion of ramipril+metabolites for (R+P) and (R+S) was 25.2 and 24.1% of dose. The maximum percentage inhibition of ACE-activity for (R+P) was 94.6%, and for (R+S) it was 94.1%. It is concluded that concomitant administration of simvastatin and ramipril has no clinically relevant effect on the pharmacokinetics or ACE-inhibition of the latter drug and its metabolites.

The pharmacokinetics of cefpirome were studied in healthy male subjects following single (0.5, 1.0 and 2.0 g) and multiple (1.0 g every 12 h for 3.5 days) intramuscular injections. High pressure liquid chromatography was used to determine cefpirome concentrations in plasma and urine. Cefpirome was absorbed rapidly, mean peak times were 1.6-2.3 h. Pharmacokinetics were linear over the 0.5 to 2.0 g range with mean total body clearance ranging from 148 to 154 mL/min. The peak plasma concentration and area under the curve increased in a dose proportional manner. The terminal half-life (2 h) was not influenced by dose or duration of dosing. There was no drug accumulation after multiple in administrations. About 70-80% of an administered dose was excreted in the urine as unchanged cefpirome. Cefpirome was well tolerated, slight to moderate pain being reported in less than 30% of the injections.

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.

After intravenous injection of a single dose of 2.0 g cefpirome (HR 810) and multiple doses of 2.0 g b.i.d. (11 doses) to 10 healthy male volunteers in an open design, concentrations of unchanged drug were measured at various times in serum and urine over 24 and 96 h, respectively. Cefpirome concentrations were determined using high-pressure liquid chromatography (HPLC). The biological half-life (t1/2, beta) found by fitting a two-compartment open model to the data was 2 h. No accumulation of the serum levels could be detected during the multiple-dose phase. Urinary concentrations of unchanged cefpirome effective against most clinically relevant bacteria were detected for at least 36 h. The drug was safe and well tolerated. No drug-related changes were observed for blood pressure, heart rate, ECG, haematology, clinical chemistry or urinalysis, including beta 2-microglobulin in serum and creatinine clearance.

The pharmacokinetics of ramipril (HOE 498) were studied after oral administration of a single 10 mg dose to 24 hypertensive patients with different degrees of renal function. The creatinine clearance ranged between 4.1 and 126 ml/min/1.73 m2 and was below 35 ml/min/1.73 m2 in 16 patients. Angiotensin converting enzyme activity and the concentrations of ramipril and its active diacid metabolite ramiprilat were measured in plasma up to 10 days after drug intake. Urine levels of ramipril, ramiprilat, their glucuronides and 2 major metabolites (a diketopiperazine and a diketopiperazine acid) were measured up to 4 days after medication. The plasma concentration-time curve of ramiprilat was poly-phasic with an initial steep decline after the peak level and a subsequent very long terminal phase at low concentrations. Impaired renal function resulted in higher peak levels of ramiprilat, longer times to peak and a markedly slower decline of plasma ramiprilat levels. Hence, the duration of angiotensin converting enzyme inhibition was considerably prolonged in renal failure and depended on the severity of renal impairment. The urinary excretion of ramipril and its metabolites decreased with decreasing renal function and was linearly related to the creatinine clearance, suggesting an alternative pathway of elimination. The pattern of excretion rates of ramipril and its various metabolites was not affected by renal failure. In contrast to the marked changes in the renal elimination, no relevant differences were observed in the absorption of ramipril from the gastrointestinal tract. Systolic and diastolic blood pressure decreased in all groups. The single 10 mg dose of ramipril was well tolerated.

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.

The humoral and antihypertensive activities of the angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0] octane-3-carboxylic acid (ramipril, Hoe 498) were investigated in 10 patients with essential hypertension (WHO stage I or II). After a 7-day placebo period, the patients were treated with 5 mg ramipril orally once daily for 14 days. Peak serum concentrations of the active metabolite M1 (dicarboxylic acid) of 5.4-62.0 ng/ml were observed 2-6 h after the first oral dose. The maximum ACE inhibition of 95% was reached 2-4 h after the first oral dose, inhibition exceeded 70% 24 h after dosing. The maximum drop in the systolic and diastolic blood pressure (random zero sphygmomanometer) was measured 4 h after ramipril (p less than 0.02, p less than 0.01), but blood pressure on days 7 and 14 of the treatment period was not different from pretreatment values. Automatically recorded blood pressure results showed a marked reduction of both systolic and diastolic blood pressure during treatment compared to placebo. No side effects occurred. From the present data it is concluded that ramipril is a potent ACE inhibitor in hypertensive patients and that further controlled studies are required for the evaluation of the antihypertensive effect of 5 mg ramipril in essential hypertension.

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.

Hoechst AG, 6230 Frankfurt (M) K. Felder Sanatorium Seeheim, 8180 Tegernsee, Federal Republic of Germany

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.

A radioimmunoassay (RIA) has been developed for the measurement of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)- 2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498) and its active metabolite (diacid: hydrolysis product of ramipril) in serum or plasma. Antibodies to the diacid were raised in rabbits against a lysine analogue conjugated to bovine serum albumin. A 125I-ramipril-diacid derivative was used as radioligand. Separation of the antibody-bound and free radiolabeled ligand was achieved by employing a polyethylene glycol solution. The RIA is specific for the active metabolite (diacid). Studies on specificity showed less than 0.6% cross-reactivity with intact ramipril or with dioxopiperazine metabolites. The levels for intact ramipril were obtained by prior enzymatic hydrolysis to the diacid. The sensitivity of the assay was 0.1 and 0.5 ng/ml for diacid and ramipril, respectively. Intra- and inter-assay coefficients of variation ranged from 3 to 14% at 1 to 30 ng diacid per ml. A recovery experiment yielded an average of 103%. The assay has been used to investigate the pharmacokinetic profile of both ramipril and its pharmacologically active metabolite.

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.

A simple and highly sensitive radioimmunoassay (RIA) procedure has been developed for the determination of the new antihypertensive drug 2-[(2-chloro-4-methyl-3-thienyl)amino]-2-imidazoline (tiamenidine) in serum, plasma and urine. Antisera to tiamenidine were produced in rabbits against its derivatives conjugated to bovine serum albumin. Studies with metabolites and imidazoline derivatives have shown that the antibodies thus produced are specific for tiamenidine. 3H-Labelled drug was used as tracer. The separation of free from antibody-bound tiamenidine was carried out by using polyethylene glycol. The radioimmunoassay (RIA) allows the determination of tiamenidine in 100 microliter biological specimens directly and without extraction down to a detection limit of 20 pg/ml. Reproducibility and accuracy of the assay are good. A sufficient correlation (r = 0.95) was obtained when serum samples were assayed by the RIA and the GC-MS method. The pharmacokinetic profile of the drug was determined in subjects after oral administration of 1 mg tiamenidine using the newly developed RIA. The course of serum levels up to 24 h after treatment may be well described by a Bateman function with an elimination half-life of about 3-5 h. These values correspond sufficiently well with the data obtained from the rate constant of the excretion via urine.

Chemischer InformationsdienstVolume 10, Issue 23 Reviews ChemInform Abstract: PRODUCTION AND IMPORTANCE OF TRITIUM-LABELED COMPOUNDS K. E. WEIMER, Search for more papers by this authorH. G. ECKERT, Search for more papers by this author K. E. WEIMER, Search for more papers by this authorH. G. ECKERT, Search for more papers by this author First published: June 5, 1979 https://doi.org/10.1002/chin.197923342Read the full textAboutPDF 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 onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume10, Issue23June 5, 1979 RelatedInformation

Radioimmunologic assay techniques are superior to most analytical procedures with regard to sensitivity, precision, general applicability, and experimental simplicity. Both for diagnosis and for monitoring of therapy this method has greatly advanced our understanding of endocrine physiology. Besides its use in clinical chemistry, radioimmunoassay is also employed in pharmacology, toxicology, and in pharmacokinetics of new drugs.