Biomedical subjects

D Brockmeier

Publications and source records attributed to D Brockmeier.

At least 19 recordsLinked to original sources

PubMed1994

Characterization of cyclosporine A uptake in human erythrocytes.

More than 70% of cyclosporine A (CsA) is bound to erythrocytes at whole blood concentrations of 50-1000 ng.ml-1. Cytosolic CsA is bound to the erythrocyte peptidyl-prolyl cis-trans isomerase cyclophilin. Measurements of serum CsA levels under clinical conditions are hampered by a temperature-dependent translocation of CsA into erythrocytes during cooling of the probes to room temperature. In order to characterize the kinetics of CsA uptake and to find a specific uptake inhibitor, we developed a method to measure the velocity of uptake based on rapid cooling of the erythrocyte suspension. The total erythrocyte-binding capacity for CsA amounted to 43 x 10(-5) nmol per 10(6) erythrocytes or 2.6 x 10(5) molecules per erythrocyte. Whereas the erythrocyte-binding capacity of CsA was temperature-independent between 10 degrees C and 42 degrees C, uptake kinetics of CsA were temperature-dependent. The Arrhenius plot for CsA uptake in human erythrocytes was linear and no transition temperature between 0 degree C and 42 degrees C could be detected. Therefore the CsA uptake process in human erythrocytes did not fulfil the criteria of carrier-mediated transport. This indicates that CsA diffuses passively into human erythrocytes. Hence, erythrocyte CsA uptake cannot be specifically inhibited.

Chromatography, High Pressure Liquid↗

PubMed1994

The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.

The impact of gender, use of oral contraceptive steroids (OCS), coffee consumption and of smoking on the metabolism of sparteine, caffeine, and paracetamol was studied in 194 randomly selected subjects (98 male and 95 female). Thirty-eight of the male volunteers were cigarette smokers, 40 of the female subjects were smokers and/or users of OCS. The metabolic ratio of sparteine oxidation (MRs) showed a trimodal distribution. 7.7% of the subjects had a MRs > 20 and thus were poor metabolizers (PMs). Within the extensive metabolizer (EM) subjects, a distinct subgroup accounting for 11% was observed with 20 > MRs > 1.2. Six of the 15 phenotypical PMs were heterozygous EMs by genotyping. This indicates the existence of one or several CYP2D6 mutations which cannot be identified by the currently employed genotyping methods. In each subgroup, i.e. smokers/OCS and non-smokers/non-OCS, the cumulative frequency distribution of the heterozygous (wt/B) phenotype caused a shift to higher MRs compared with the wild-type homozygotes (wt/wt). Thus, for the in vivo activity of CYP2D6, genetic determinants prevail over environmental factors. Smoking, use of oral contraceptive steroids, caffeine consumption, or gender had no influence on sparteine metabolism. The distribution of the paracetamol glucuronide/paracetamol metabolic ratio appeared to be unimodal although skewed. Glucuronidation capacity was clearly affected by gender, OCS use and smoking. It was higher in male than in female subjects. Male smokers had the highest, and female non-smokers/non-OCS users the lowest metabolic ratio. CYP1A2 activity, as determined by a caffeine metabolic ratio ((AFMU + 1X + 1U)/1, 7U), was multimodally distributed and was clearly increased in smokers. It was significantly correlated to paracetamol glucoronidation in male heavy smokers (r=0.85), suggesting an element of co-regulation of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransferase isozymes, including UGTI.6.

Acetaminophen↗

PubMed1993

Substrate affinity of the protein tyrosine kinase pp60c-src is increased on thrombin stimulation of human platelets.

Human blood platelets contain high levels of non-receptor protein tyrosine kinases of the Src family, particularly pp60c-src, suggesting an important role for these enzymes in platelet physiology. Indeed, in response to various agonists of platelet function, a number of proteins become phosphorylated at tyrosine residues. However, no enzymic activation of an Src-related tyrosine kinase has yet been shown in platelets. In searching for the kinase(s) responsible, we found that all agonists tested that directly or indirectly activate protein kinase C in platelets (phorbol 12-myristate, 13-acetate, thrombin, vasopressin, collagen, calcium ionophore A23187) increased the overall activity of pp60c-src determined by IgG phosphorylation in an immunocomplex assay in the presence of low ATP concentrations. On the other hand, elevation of cyclic AMP directly by forskolin or indirectly by prostaglandin E1, or elevation of cyclic GMP by sodium nitroprusside did not significantly affect the activity of the enzyme. To substantiate the differences in enzyme activity, we determined Km and Vmax, values of pp60c-src from resting and thrombin-stimulated platelets. Thrombin treatment increased substrate affinity of pp60c-src as indicated by a 2- to 3-fold decrease in the Km values for ATP and the exogenous protein substrate casein. Vmax. values were only slightly altered under the assay conditions used. To further rule out modifications of pp60c-src in phosphorylation as a probable cause of the changed substrate affinity, we analysed tryptic phosphopeptides of immunoprecipitated, 32P-labelled pp60c-src of unstimulated and stimulated platelets. The platelet agonists listed above induced an increase in pp60c-src phosphorylation at Ser-12, which is the amino acid phosphorylated by protein kinase C. Surprisingly, we found that elevation of cyclic AMP did not affect 32P labelling of pp60c-src. On the basis of our data, we suggest that phosphorylation at Ser-12 might be one of the signal-triggering events that cause the increase in substrate affinity of pp60c-src.

Adenosine Triphosphate↗

PubMed1993

Multiple-dose pharmacokinetics of ramipril in patients with chronic congestive heart failure.

Thirteen patients with chronic congestive heart failure of NYHA class II-III received multiple doses (14 days) of ramipril (5 mg once daily); the concentrations of ramipril and ramiprilat in plasma, as well as ramipril, ramiprilat, glucuronides, diketopiperazine, and diketopiperazine acid in urine were measured at various times for 14 days. One patient dropped out after the first day due to hypotension and another who accidentally received another ACE inhibitor additionally was excluded, so that 11 patients completed the study. Ramipril and ramiprilat in plasma were determined by radioimmunoassay, and ramipril and its metabolites in urine were measured by gas chromatography in the laboratories of Hoechst AG. Peak concentrations of the active substance ramiprilat were reached after about 4 h and amounted to 22.3 +/- 11.1 ng/ml after the first dose, and a peak concentration of 26.6 +/- 10.0 ng/ml was observed 2.5 +/- 1.4 h on average after administration on day 14. Practically no accumulation was observed for ramiprilat; the AUD (0-24 h) values increased from 191.3 +/- 83.1 ng.h/ml for the first study day to 238.3 +/- 98.0 ng.h/ml for day 14. As expected, only very small fractions of the dose were excreted with urine as unchanged ramipril and ramipril glucuronide. Ramiprilat is excreted with urine to a larger extent than is rampiril--on average 6.6 +/- 3.0% on the first day and 12.2 +/- 3.8% on day 14. The total amount excreted increased by 34% on average, and was mainly due to an increased ramiprilat excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

Pharmacokinetic profile of cefodizime.

The pharmacokinetics of cefodizime (CDZ) were determined after i.v. and i.m. administration of single doses of up to 2 g and after i.v. administration of 2 g b.i.d. for six days. Serum concentrations were adequately described by three exponential functions, with a terminal half-life of about 4 h. Serum and urine levels and amounts excreted were dose-proportional, and derived pharmacokinetic characteristics were dose-independent. Steady state was established after the second dose (b.i.d.). CDZ is 100% bioavailable after i.m. administration. Concomitant administration of lidocaine did not alter either bioavailability or pharmacokinetic characteristics. Following administration of 1 and 2 g i.m., Cmax was reached after 1.2 h and amounted to 60 and 140 mg/l, respectively. CDZ is 88% bound to plasma proteins. CDZ was predominantly eliminated by the kidneys (80% of dose), a further 20% being excreted in the bile. Metabolites were not detectable in serum or urine. Dose adjustment does not seem warranted in the elderly. For renally impaired patients with CLcr between 30 and 10 ml/min, the daily dose should not exceed 2 g. For patients with CLcr below 10 ml/min, individual adjustment is suggested. CDZ showed good penetration into tissues and biological fluids (lung, bronchial secretions, pleural fluid, kidney, prostate, urine, bone, muscle, skin, Fallopian tube) with long-lasting concentrations. In urine, therapeutic concentrations were present for more than 24 h after administration of 1 and 2 g. Thus, on the basis of its pharmacokinetic profile, cefodizime is appropriate for effective treatment with once-daily administration.

Age Factors↗

PubMed1992

Pharmacokinetic profile of a novel slow release preparation of molsidomine.

A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (greater than 5 ng.ml-1) were not maintained over 24 h by this slow release formulation.

Adult↗

PubMed1992

Influence of ramipril on plasma atrial natriuretic peptide, antidiuretic hormone, angiotensin II and aldosterone in patients with chronic congestive heart failure.

UNLABELLED: In an open trial 5 mg ramipril daily for 2 weeks was administered to 11 patients with congestive heart failure. 24-hour plasma profiles of atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), angiotensin II (Ang II) and aldosterone (Aldo) were determined before and on days 1 and 15 of ramipril treatment, respectively. Urinary sodium excretion was also measured at the same time points. There were no relevant differences in the 24-hour profiles of ANP and ADH. Ang II values dropped as expected on the first day of ramipril treatment from 11.2 pg/ml to 2.9 pg/ml at 3 h post administration and from 6.7 pg/ml (predose) to 1.8 pg/ml at 2 h post administration on day 15. Plasma aldosterone values increased slightly from day 1 to day 15, sodium excretion increased from 125.9 mmol to 166.5 mmol/24 h; however, both changes in the 24-hour profiles were nonsignificant. A clinically relevant improvement in the severity of CHF was observed. From a total of 121 reported symptoms according to McKee et al., 35 showed an improvement; 81 remained unchanged, in only 5 symptoms a deterioration was observed. According to the NYHA-classification 5 patients improved from grade III to II, 6 remained unchanged. CONCLUSION: ACE inhibition does not induce changes in ANP or ADH levels in the resting state while Ang II decreases. A slight increase in aldosterone levels may be due to increased sodium excretion.

Aged↗

PubMed1991

Influence of ramipril on renal function in patients with chronic congestive heart failure.

Ramipril was administered to 13 patients, aged 49-80 years, weighing 53.5-90.3 kg, with congestive heart failure (CHF) for 2 weeks in an open trial. One patient dropped out after day 1 and another accidentally received another angiotensin-converting enzyme (ACE) inhibitor, so that 11 patients remained for analysis. Each patient received 5 mg of ramipril daily for 2 weeks, followed by a 1-week washout period. Urine was collected in 4-h fractions for 12 h followed by a 12-h fraction on days 1, 8, and 15. Creatinine clearance, as well as the excretion of albumin and the urinary brush border enzymes gamma-glutamyl transferase (GGT), alanine aminopeptidase (AAP), N-acetyl-beta-D-glucosaminidase (NAG), and lactate dehydrogenase (LDH) were determined. The values for albumin excretion, creatinine clearance, GGT, AAP, NAG, and LDH obtained for the various days during the time course before and during multiple dosing were subjected to an analysis of variance followed by Scheffe's test for means. Daily albumin excretion decreased during treatment with ramipril from 23.8 +/- 27.4 mg/24 h (baseline) to 12.9 +/- 15.1 (day 1), 10.8 +/- 15.6 (day 8), and 12.4 +/- 12.7 mg/24 h (day 15). The differences were significant (alpha = 0.05) when compared to pretreatment albumin excretion. Creatinine clearance increased from 78.8 +/- 38.3 ml/min (baseline) to 82.4 +/- 34.6 (day 1), 85.1 +/- 28.5 (day 8), and 91.7 +/- 36.4 ml/min (day 15). The change on day 15 was significant (alpha = 0.05) when compared to pretreatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosamine↗

PubMed1990

Evidence for muscarinic receptors in endothelial cells from combined functional and binding studies.

The aim of this study was to characterize muscarinic receptors of the bovine coronary artery by means of a combination of mechanical relaxation and contraction responses and radioligand binding data. Fresh helical strips of bovine coronary artery with intact endothelium relaxed in response to low concentrations (0.03-1 microM) of acetylcholine (ACh) and contracted at higher concentrations while endothelium-denuded strips only contracted. The ED50 for relaxation was 0.13 microM and that for contraction 1.8 microM (without endothelium); in the presence of endothelium, contraction dose-response curves were shifted to the right and the maximum contraction was reduced. In order to determine the location of the receptors mediating vasorelaxation, apparent affinity constants (KA) of ACh for relaxant and contractile effects were determined by irreversible blockade of a fraction of receptors with propyl benzilylcholine mustard (PBCM). The affinity constants (KA) were 0.22 microM for relaxation and 13 microM (with endothelium) and 20 microM (without endothelium) for contraction. In competition binding experiments against the muscarinic antagonist, [3H]N-methylscopolamine ([3H]NMS), the apparent affinity (KI) of ACh for binding sites in homogenates of endothelium-free coronary artery was 16 microM which was not different from the affinity constant determined in functional contraction experiments. Thus, the affinity constant of ACh determined for relaxation responses with endothelium-preserved vessels had no correlate in the binding affinity as determined with endothelium-free arteries. These findings indicate that bovine coronary arteries are relaxed by ACh through muscarinic receptors located on the endothelium whereas contractions are mediated by receptors on smooth muscle cells.

Acetylcholine↗

PubMed1990

Pharmacokinetics of prenylamine racemate and enantiomers in man.

Pharmacokinetics of racemic prenylamine were investigated in 6 healthy volunteers. Plasma levels were determined by gas chromatography/mass spectrometry. Concentration-time profiles were analyzed both by compartment-dependent and compartment-independent pharmacokinetic models. Terminal elimination half-life was 14.1 h (SD: 6.9 h). The apparent total clearance was 5.8 l/min. Mean residence time of racemic prenylamine was found to be 14.7 h (SD: 3.8 h). The relative bioavailability of prenylamine (Segontin 100) was 82.2% (SD: 9.9%) determined in six healthy volunteers. The volunteers received simultaneously the film tablet and 100 mg racemic dideuteroprenylamine as an aqueous solution of the lactate. This procedure is known to exclude intraindividual changes in absorption, first-pass metabolism or volume of distribution that might occur on sequential administration. The absolute bioavailability was estimated to be in the order of 15%. In a pilot study the pharmacokinetics of the enantiomers were investigated in 2 healthy volunteers. S-(+)-prenylamine was eliminated considerably faster from plasma than R-(-)-prenylamine suggesting a stereoselective metabolism. The AUC of the (+)-enantiomer was 20% of that of the R-(-)-prenylamine.

Adult↗

PubMed1989

Pharmacokinetic characteristics of roxatidine.

This article reviews the published and unpublished results of pharmacokinetic studies with roxatidine acetate in healthy volunteers of different ethnic origins, patients with various degrees of renal impairment, patients on maintenance hemodialysis, lactating women, and elderly patients. In addition, it reports on the findings of interaction studies with food and other drugs. The pharmacokinetic characteristics of roxatidine were found to be nearly identical for different doses, formulations, and ethnic groups. The decrease in relative total clearance (oral clearance) in patients with renal impairment and in the elderly can be explained almost completely by their level of renal function. As expected from the pharmacokinetic characteristics in healthy volunteers, only a small amount of roxatidine is removed by hemodialysis. Dose reduction is recommended in patients with renal impairment, but dose supplementation after hemodialysis is not necessary. Only a negligible fraction of the dose administered is excreted with breast milk. No pharmacokinetic interactions were found with theophylline, warfarin, propranolol, diazepam, and desmethyldiazepam, antipyrine or antacids. Food did not interfere with the absorption or disposition of roxatidine.

Aged↗

PubMed1988

Estimating reduced availability due to first pass elimination from relative total clearance and renal clearance.

A simple formula is presented for estimating the systemic availability of an orally administered drug from the relative total clearance (oral clearance) when renal clearance forms an important part of total clearance. Hepatic plasma flow is used in the equation and is represented by an average value taken from the literature. The formula is applied to data for cimetidine discussed in the literature. A further application is demonstrated for a drug under development for which an intravenous formulation was not available. It is possible to estimate the upper and lower limit of availability if some information on the amount of drug absorbed is available.

Administration, Oral↗

PubMed1988

Penbutolol: pharmacokinetics, effect on exercise tachycardia, and in vitro inhibition of radioligand binding.

The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by plasma have been investigated in 7 healthy volunteers. The peak penbutolol concentration of 285 ng/ml was observed 1.2 h after administration, and the maximum of 4'-OH-penbutolol of 4.76 ng/ml was found after 1.64 h. Penbutolol was detected for up to 48 h, and 4'-OH-penbutolol dropped below the limit of detection after about 10 h. The terminal plasma concentration of penbutolol declined with an average half-life of 19 h. The maximum reduction in exercise-induced tachycardia was 33 beats/min 2.6 h after taking penbutolol. There was still a significant reduction of about 7 beats/min after 48 h. This effect could be adequately explained by the concentration-time course of penbutolol in combination with Clark's model of the concentration-effect relationship. Antagonist activity in plasma caused 91% inhibition of radioligand binding in vitro to beta 2-adrenoceptors on rat reticulocyte membranes 1.6 h after intake of penbutolol. By 48 h after intake, radioligand binding was still significantly inhibited (23%). The in vitro inhibition of radioligand binding by plasma showed a linear correlation with the reduction in exercise-induced tachycardia for all phases of the workload. The time course of the reduction in heart rate was completely explained by the in vitro inhibition of radioligand binding. However, it was not possible to explain the in vitro inhibition of radioligand binding by the concentration-time course of penbutolol using a simple competition model, although both variables were based on the same sampling site. When the in vitro inhibition of radioligand binding was plotted against the penbutolol concentration at the same sampling times (with both variables transformed to multiples of the apparent inhibition constant) the discrepancy became even more apparent as time-related counterclockwise hysteresis. None of the known metabolites of penbutolol can explain the discrepancy between the penbutolol concentration and the inhibition of radioligand binding in vitro. It appears that an other active metabolite is formed, which contributes to the effect in vitro and in vivo and so can explain the observed discrepancy.

Adrenergic beta-Antagonists↗

PubMed1988

A pharmacokinetic study of roxatidine acetate in chronic renal failure.

The pharmacokinetics of a single oral dose of roxatidine acetate 150 mg were studied in 31 patients with varying degrees of chronic renal failure. The patients were divided into 5 groups according to their creatinine clearance (Clcr): controls (Clcr 94.5 +/- 13.9 ml/min; n = 6); mild chronic renal failure (Clcr 47 +/- 6 ml/min; n = 4); moderate chronic renal failure (Clcr 27.3 +/- 3.1 ml/min; n = 4); severe chronic renal failure (Clcr 12.8 +/- 1.4 ml/min; n = 5) and uraemia (Clcr 6.6 +/- 0.6 ml/min; n = 12). Serum and urine samples were analysed with capillary gas chromatography to measure the salt of the desacetyl metabolite of roxatidine acetate (roxatidine). The terminal half-life was 6.02 +/- 0.31 hours in controls and 7.35 +/- 0.57, 9.3 +/- 0.83, 14.6 +/- 3.7 and 18.10 +/- 2.77 hours, respectively, in the 4 other groups, with progressively decreasing creatinine clearance. Maximum serum concentration and time to maximum serum concentration rose from 816 +/- 75 ng/ml and 2.08 +/- 0.22 hours, respectively, in controls to 1364.7 +/- 156 ng/ml and 4.05 +/- 0.47 hours, respectively, in uraemic patients. Relative total clearance progressively decreased with decreasing glomerular filtration rate (GFR) [from 353.6 +/- 26 ml/min in controls to 90.31 +/- 12.2 ml/min in patients with uraemia]. Renal clearance decreased from a control of 243.9 +/- 56 ml/min to 12.32 +/- 0.18 ml/min in uraemic patients. A linear correlation between creatinine clearance and both relative total clearance and renal drug clearance was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Pharmacokinetics of histamine (H2)-receptor antagonists, including roxatidine, in chronic renal failure.

In this paper the effects of chronic renal failure on the pharmacokinetics of H2-antagonists are reviewed and the results obtained with roxatidine presented. In normal renal function renal clearance is around 60-80% of total plasma clearance of all H2-antagonists. Consequently, prolongation of serum half-life, mainly due to a decrease in urinary excretion, is noted in patients with decreasing glomerular filtration rate. In chronic renal failure, a dose reduction is therefore necessary with all H2-antagonists, including roxatidine. It appears that neither haemodialysis nor peritoneal dialysis substantially influences the pharmacokinetics of these drugs. Therefore, the same dosage schedule as in uraemia may be applied in patients with dialysis. Finally, in the elderly the dosage of all H2-antagonists should be adapted to the expected decrease in renal function.

Anti-Ulcer Agents↗

PubMed1986

The absorption of piretanide from the gastro-intestinal tract is site-dependent.

The absorption of piretanide was investigated after placing the drug in the stomach, duodenum and ascending colon under visual control. The relative amounts absorbed and the rates of absorption were estimated from the area under the curve and the total mean time, respectively. Similar amounts of piretanide were absorbed and at almost the same rate after placement in the stomach and duodenum; the area under the curve for the stomach was 250 ng h/ml and for the duodenum 243 ng h/ml, the mean absorption times being 1.97 h and 1.51 h respectively. A marked difference was observed in the rate of from the ascending colon; the area amounted to 66 ng h/ml and the mean time to 3.99 h. Although area values for the colon were significantly different from those observed with the stomach and duodenum, it must be emphasised that the amount absorbed depends on the time the drug is in contact with the absorbing surface. There is discussion of whether the differences in absorption between the duodenum and colon can be explained by the physico-chemical properties of the drug alone, or whether the results reflect a saturable transport mechanism.

Adult↗

PubMed1986

Mean residence time.

The definition of mean residence time in the strict sense of mathematical statistics is deduced. It is demonstrated that the area-normalized concentration time curve is an estimate of the probability density function for residence times of drug molecules in the pharmacokinetic system, provided that the area under the concentration-time profile is proportional to the total amount eliminated from the system. Criticisms (8) on the determination of the mean residence time are refuted. The linearity of pharmacokinetic systems is defined, based on the statistical interpretation of these systems.

Humans↗

PubMed1986

Model-free evaluation and mean-time concept in pharmacokinetics.

Pharmacokinetic characteristics may be separated into three classes: firstly, those which are truly independent of pharmacokinetic modelling - curve characteristics for instance, such as Cmax or tmax, but also organic clearance values; secondly, those which can be evaluated without an explicit pharmacokinetic model but under basic assumptions - characteristics such as total clearance, mean and variance of residence times or total volume of distribution; and thirdly, those which are bound to elaborate pharmacokinetic models, such as hybrid constants, micro-constants or partial volumes of distribution. It can be demonstrated that the second class - the model-independent evaluated characteristic - and the third are mutually transferrable; examples of this transcription are given. However, these purely theoretical considerations can only demonstrate that the second class is consistent with classic pharmacokinetic modelling. The usefulness of the model-independent evaluated characteristic is underlined by results of clinical pharmacological investigations in which this technique was applied. The topics addressed by these studies cover the problems of deep compartments, differences in absorption, influence of disease, drug interaction, and first-pass metabolization. Since the mean-time concept in particular is still controversial in the literature, some general theoretical explanations seem to be necessary.

Humans↗