Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration.

Amlodipine, 3-ethyl 5-methyl-2-[(2-aminoethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methy l-3,5-pyridinedicarboxylate, is a chiral calcium antagonist, currently on the market and in therapeutic use as a racemate. The pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration to healthy male human volunteers together with comparative administration of the racemic mixture of both enantiomers were studied. Plasma levels were studied as a function of time and assayed using an enantioselective chromatographic method (coupled chiral and achiral HPLC) with on-line solid-phase extraction and UV absorbance detection. The method was validated separately for the R-(+)- and S-(-)-enantiomer, respectively. Results of the study indicate that the pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration is comparable to that of each enantiomer after administration of the racemate. No racemization occurs in vivo in human plasma after single enantiomer administration.

[Changes in plasma proteins and drug distribution in kidney and liver diseases]. / Promjene plazmatskih proteina u bolestima bubrega i jetre i distribucija lijekova.

Kidney and liver diseases induce alterations in drug binding to plasma proteins. These alterations are caused by qualitative and quantitative changes of plasma proteins and the presence of endogenous substances which act as competitive inhibitors of drug binding to plasma proteins. These changes are the most prominent in nephrotic syndrome and uremia among kidney diseases and in cirrhosis among liver diseases. The more important drugs in which the free fraction is changed in these entities are listed in the tables. The changes in drug distribution caused by plasma protein alterations may induce significant changes in entire drug pharmacokinetics. Discussed are theoretically expected and experimentally proven changes in plasma proteins in kidney and liver diseases and their influence to drug action and dosing regimen.

The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine.

The effect of food and metoclopramide on the pharmacokinetics of bromocriptine was investigated in 7 healthy subjects. Plasma concentrations of bromocriptine were measured by radioimmunoassay after a single oral dose of 7.5 mg bromocriptine. Maximal plasma concentrations of bromocriptine were slightly lower when the drug was given after breakfast. Bioavailability of the drug was not significantly reduced by food nor by metoclopramide pre-treatment. Side effects of bromocriptine were considerably reduced by metoclopramide pre-treatment (0.5 mg/kg); the decrease was about 83% as estimated from Table II.

Bioavailability of dihydroergosine in healthy volunteers.

Eight healthy volunteers received an oral dose of 10 mg and an intravenous dose of 0.75 mg of dihydroergosine. Plasma concentrations were measured by HPLC method, and some pharmacokinetic parameters were calculated. The biologic half-life in the elimination phase was 8.35 +/- 1.87 h after oral administration and 8.84 +/- 3.64 h after intravenous administration. In both cases of administration a secondary rise in plasma concentration of dihydroergosine was observed, which can be attributed to hepatic recycling. The calculated bioavailability of the drug was 9.80 +/- 2.8%.

Dose-dependent bioavailability of propranolol.

The pharmacokinetics of orally administered propranolol in doses of 10, 40, 80 and 160 mg was studied in eight healthy volunteers in a cross-over trial. The analytical method applied made possible a parallel determination of propranolol and of 4-OH propranolol. The dose-dependent kinetics of orally administered propranolol was demonstrated. In our study linear dependence could be established only within a dosage range of 40 mg to 160 mg. Both substances determined in plasma, propranolol as well as 4-OH propranolol, show a tendency toward non-linearity, particularly at the lower dosage range between 10 and 40 mg.

HPLC method for determination of ergot alkaloids and some derivatives in human plasma.

Ergot alkaloids and their dihydrogenated methanesulphonate (ms) salts were determined and measured in human plasma. High-performance liquid chromatography (HPLC) with fluorometric detection was used for separation of ergot alkaloids in plasma. Several ergot alkaloids and their derivatives, including lysergide (LSD), can be identified in cases of poisoning.

Pharmacokinetics of dihydroergosine in rats after intravenous and oral administration.

Wistar rats received an intravenous dose of 20 micrograms/kg and an oral does of 40 micrograms/kg 3H-Dihydroergosine. Concentrations of radioactivity were measured in plasma, bile, urine, and faeces, and pharmacokinetical parameters of an open two compartment model were calculated. After intravenous injection and oral administration 3H-Dihydroergosine is rapidly lost from the central compartment with distribution rate constants alpha = 0.889 h-1 and beta = 0.722 h-1, respectively. Biological half life in the elimination phase after both application is nearly the same t 1/2 = 13.6 h. The volume of central compartment is Vc = 3.075 l/kg and the volume of distribution Vd beta = 30.75 l/kg. The fraction of 3H-Dihydroergosine absorbed after oral administration, calculated from areas under the curves upon oral and intravenous administration, is 31%. The percentage of 3H-radioactivity eliminated with bile was 98.3% of the dose within 72 hours after intravenous and 29.3% after oral administration. The main portion of the administered 3H-radioactivity was recovered in faeces -66.1% after intravenous and 81.3% after oral administration, while only 17.4% and 4.9% of the administered dose was eliminated in the urine within 120 hours, respectively.

Dihydroergosine pharmacokinetic modelling and simulation.

For this study of dihydroergosine pharmacokinetic modelling and simulation, the data from our paper about 3H-DHESN plasma, bile, urine, and faeces concentrations after intravenous and oral administration were used (1). The model obtained with the identified parameters was in agreement with in vivo data. Certain special phenomena, such as the enterohepatic cycle and incomplete absorption, were taken into account. Analog-hybrid simulation and identification represents an effective tool for such studies. In spite of the limited validity of the available in vivo data, the work represents a first step in the introduction of DHESN into human medicine.

Comparison of the bioavailability of Redergin tablets (1.0 mg) and Redergin solution.

Pharmacokinetic investigations of Redergin LEK oral tablets (1.0 mg, dihydroergotoxine methanesulfonate) described in this article proved the efficacy of this pharmaceutical formulation. The properties of Redergin tablets almost completely correspond to results obtained when the active substance is applied as solution. The bioavailability of the formulation Redergin oral tablet is only a few percent lower than that of Redergin solution. A comparison with intravenous application of dihydroergotoxine methanesulfonate established that the bioavailability of Redergin oral tablet (1.0 mg) is 34% and Redergin solution 38%.

Clinical pharmacokinetics of nitroxoline.

14C-Nitroxoline was given orally to the rats, and its distribution as well as plasma and bile levels were determined autoradiographically and by the aid of radioactivity measurements, respectively. Nitroxoline was also given to the human volunteers orally and intravenously in three various doses and the corresponding urine concentrations of unconjugated and conjugated nitroxoline were determined spectrophotometrically. A pharmacokinetical model was generated on the basis of the results. The curve fitting procedure between total nitroxoline cumulative quantities in urine and the model response simulated on analog-hybrid computer enabled the evaluation of the validity of the chosen model as well as of the identification of its parameters.

[Pharmacokinetics and metabolism of trazodone in man (author's transl)]. / Pharmakokinetik und Stoffwechsel von Trazodone beim Menschen

After intravenous, intramuscular and oral administration of 25 mg 14C-labelled 2-(3-[4-(m-chlorophenyl)-1-piperazinyl]-propyl)-s-triazolo[4,3-a]pyridin-3-(2H)-one-hydrochloride (trazodone), plasma levels, elimination and metabolite pattern in plasma and urine were investigated. The plasma levels after all routes of administration are almost identical. The absorption of the compound is fast and complete. The elimination of radioactivity occurs in a biphasic manner with a half-life of 1 h for the earlier and 13 h for the second phase, no matter what application route had been chosen. The comparison of the plasma levels of fasted and non-fasted subjects shows a shift of the plasma maximum from 1.5 to 2.5 h following administration and a decrease in the maximum level of 30%. The radioactivity is excreted predominantly by renal processes (70-75% within 72 h). The main product in plasma is unchanged trazodone, whereas in urine it is found only in minute amounts. The radioactivity in urine is represented by conjugates that had formed after hydroxylation on the chlorophenyl residue (20%), by a dihydrodiol-metabolite of trazodone (15%) and by a carboxylic acid originating from oxidative cleavage of the parent compound (35%).

[Pharmacokinetics and metabolite pattern of clenbuterol in the rat]. / Pharmakokinetik und Metabolitenmuster von Clenbuterol bei der Ratte

Pharmacokinetics and metabolite pattern of the beta-sympathomimetic 4-amino-alpha-[tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, NAB 365) have been investigated in the rat. After a single i.v. dose of 2 mg/kg 14C-NAB 365 up to 10 min p.a. the blood level falls very steeply and 15 min p.a. there is an increase to be observed. A maximum blood level of 0.85 mug eq. NAB 365/ml is achieved. Then a biphasic elimination of radioactivity from the blood occurs. After a single oral dose of 2 mg/kg the maximum blood level of 0.5 mug/ml is attained 2 h p.a. Again a biphasic elimination occurs. 26 h is the half-life of the slower of two elimination processes for i.v. and p.o. administration, respectively. Elimination predominantly takes place via the kidneys. After i.v. administration 85% and after p.o. administration 80% of the radioactivity applied are eliminated in urine and faeces. The main portion of radioactivity had been eliminated by 48 h p.a. As can be seen from the urinary radioactivity absorption is complete. Following i.v. dosing the excretion is slightly faster than after p.o. administration. Whole-body autoradiography and the distribution of radioactivity in the organs show a relatively slow absorption after p.o. dosing. In the pregnant mouse the placenta barrier is passed but the fetuses contain far less radioactivity than the mother animal. Clenbuterol is metabolized in the rat. 70% of the radioactivity represents the unchanged parent compound in urine (38% of the administered radioactivity). 8 metabolites have been established in urine (extracts). Faeces radioactivity mainly contains unchanged clenbuterol and only traces of metabolites. The metabolite pattern of the maximum plasma level (2 h after p.o. administration) and the metabolite pattern of the collected urines are identical. 38% of the administered radioactivity represent unchanged NAB 365 in the urine, whereas there are 45% in the plasma.

[Comparison of the pharmacokinetic profiles of clenbuterol in rat and dog during toxicological studies (author's transl)]. / Vergleich des pharmakokinetischen Profils von Clenbuterol bei Ratte und Hund während toxikologischer Untersuchungen

The pharmacokinetics of the beta-sympathomimetic 4-amino-alpha-[(tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, NAB 365) have been investigated in two animal species during the chronic toxicological studies after single and multiple dosing. After oral administration of 2.5 mg/kg (dog) and 5 mg/kg (rat) the plasma levels showed significant differences. Moreover, a marked sex difference was to be seen in the plasma levels of the rat. The excretion, established only in the dog, showed no difference after single or multiple administration. The elimination occurs predominantly via the kidneys, and the main urinary elimination product is the unchanged clenbuterol. Each of the 8 metabolites is formed only in minor quantities. The biotransformation is not altered by long-term administration. The differences in the plasma levels that are observed with larger doses can be explained by the biological adaptation of the gastrointestinal tract during multiple administration.

[Radioimmuno assay of the sulfonylurea AR-DF 26(author's transl)]. / Radioimmunologische Bestimmung des Sulfonylharnstoffes AR-DF 26

A radioimmunological method was developed for 1-cyclohexyl-3-[p-(beta-4,4-dimethyl-7-methoxy-1,3-(2H,4H)-isoquinolinedion-2-yl)phenethyl]-sulfonylurea (AR-DF 26, gliquidone, Glurenorm) estimations in plasma. The antisera were obtained by immunization of rabbits with AR-DF 26-bovine serum albumin (BSA) conjugate. The estimation is based on the competitive displacement in plasma samples of known amounts of labelled AR-DF 26, bound to a specific antibody by unknown amounts of unlabelled AR-DF 26. Concentrations of as low as 1 ng of AR-DF 26 per sample can be measured by this method. The investigations into the specificity of this reaction have shown that the antiserum is extremely specific for AR-DF 26. There is good reproducibility of the results and no differences could be found by variance analysis between different measurements of the same AR-DF 26 concentration. Since more than 70% of the plasma concentration correspond to unchanged AR-DF 26 for a longer period after application, the results of this AR-DF 26-radioimmuno assay is only minimally altered by its metabolites.

[Human pharmacokinetics and metabolism of 14C-labeled gliquidone (AR-DF 26)]. / Humanpharmakokinetik und Metabolismus von 14C-markiertem Gliquidone (AR-DF 26)

Investigations of pharmacokinetics and metabolism of 14C-labelled 1-cyclohexyl-3 (p-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2-(1H)-isoquinolyl)-ethyl]-phenyl)-sulfonyl)-urea (AR-DF 26; gliquidone; Glurenorm) after i.v. and oral applications were carried out on 10 healthy volunteers. After oral application of 15 mg AR-DF 26, maximum blood levels of 370 ng/ml blood or 700 ng/ml plasma, respectively, were reached. After i.v. as well as oral application of AR-DF 26 in men the bulk of the substance applied was excreted with the faeces and only 5 percent were found in urine. After both modes of application the metabolites in the faeces were found to be quantitatively and qualitatively similar. The structure of 4 metabilites was demonstrated by isotope dilution analysis.

[Pharmacokinetics and metabolism of the antiinflammatory agents S-H 766 in man]. / Pharmakokinetik und Metabolismus des Antiphlogistikums S-H 766 beim Menschen

Blood and plasma levels as well as urinary and fecal excretion were measured in humans after oral administration of radioactively labelled 4-[j-(2'-fluorobiphenylyl)]-4-hydroxycrotonic acid (S-H 766 MO). The radioactivity in the plasma reaches maximum values of about 10 mug eq./ml 1 to 2 h after application with either form. After repeated administration good agreement is found between the plasma levels measured and those simulated according to the pharmacokinetic parameters obtained after single application. The S-H 766 metabolites were investigated in blood and urine. The substance was found to undergo considerable metabolism, only approximately 2% being excreted in the urine unchanged. The conjugates, which constitute over 60% of the radioactivity of the urine, consist mainly of glucuronides and sulfates. The structure of the aglycones shows that the metabolism occurs along two pathways, by beta-oxidation of the aliphatic side chain into aryl acetic acids and by hydroxylation of the aromatic nucleus to phenolic compounds. It must be assumed that these biotransformations take place both simultaneously and successively.

[Pharmacokinetic behaviour of gliquidone (AR-DF 26), a new sulfonyl urea. Summary of the studies so far (author's transl)]. / Pharmakokinetisches Verhalten von Gliquidone (AR-DF 26), einem neuen Sulfonylharnstoff (Zusammenfassung der bisherigen Untersuchungen)

Pharmacokinetic studies of the new antidiabetic agent gliquidone, AR-DF 26, 1-cyclohexyl-3-((p-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H)-isoquinolyl)-ethyl]-phenyl)-sulfonyl)-urea (Glurenorm) in healthy volunteers and patients with several diseases related to diabetes are reported. Plasma levels and excreta were monitored using the 14C-labelled compound and/or a specific radioimmunoassay. Following oral administration of a 30 mg tablet a maximal plasma level of approximately 600 ng/ml was attained after 2 to 3 h. The compound was eliminated mainly with the bile. Urinary excretion amounted to about 5% only. Comparison of diabetic patients with or without concomitant renal insufficiency did not reveal significant differences with respect to the pharmacokinetic behaviour of the drug. This holds true also for administration following a multiple dosage regimen where even three doses of 60 mg each a day, did not result in elevated blood levels in either group. AR-DF 16 is metabolized mainly to four products, which were identified besides unchanged drug in bile, stool and urine. All excreta showed quite a similar pattern of distribution. In plasma, however, unchanged drug accounted for at least 80% of total radioactivity up to 8 h besides some biotransformed products, mainly AR-DF 33.