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Biomedical subjects

U Gundert-Remy

Publications and source records attributed to U Gundert-Remy.

At least 19 recordsLinked to original sources
PubMed1992

The pharmacokinetics of the beta 2-adrenoceptor agonist fenoterol in healthy women.

We have studied the pharmacokinetics of fenoterol in healthy women during and after a 3 h intravenous infusion of different doses within the therapeutic range for tocolysis (0.5 microgram.min-1, 1.0 micrograms.min-1, and 2.0 micrograms.min-1). A specific and sensitive radioimmunoassay was used for the determination of fenoterol. For compartmental analysis the plasma concentration time data were fitted with the TOPFIT program, assuming two exponentials. The total clearance of fenoterol increased with dose (1299 ml.min-1 at 0.5 microgram.min-1, 1483 ml.min-1 at 1.0 micrograms.min-1, and 1924 ml.min-1 at 2.0 micrograms.min-1), as did the apparent volume of distribution (from 49 l at the lowest to 85 l at the highest dose). In contrast, the apparent half-lives were not dose-dependent, with t1/2.lambda 1 4.8 min and t1/2.lambda z 52 min.

Adult↗
PubMed1991

Elimination of flecainide as a function of urinary flow rate and pH.

In order to evaluate the influence of urinary flow rate at different pH values on the pharmacokinetics of the basic antiarrhythmic drug flecainide 7 healthy men received 50 mg flecainide under 4 different conditions: 1. acidic urine (pH 5) and a high fluid load (125 ml.h-1) 2. acidic urine (pH 5) and a low fluid load (25 ml.h-1) 3. alkaline urine (pH 8) and a high fluid load (125 ml.h-1) 4. alkaline urine (pH 8) and a low fluid load (25 ml.h-1) At acidic pH the half-life, the amount of unchanged drug in the urine (Ae), renal clearance (CLR) and area under the curve (AUC) were independent of the fluid load. At alkaline pH Ae (5.8 vs 2.6 mg) and CLR (73 vs 33 ml.min-1) were significantly affected by fluid load (high vs low), whereas half-life and AUC were not different (15.7 vs 16.0 h, 1480 vs 1540 ng.ml-1.h). When comparing acidic and alkaline urinary pH conditions, half-life, Ae, CLR, and AUC were different. For a high fluid load the values at acidic vs alkaline pH were half-life 10.0 vs 15.7 h; Ae 15.9 vs 5.8 mg; CLR 288 vs 73 ml.min-1; AUC 976 vs 1480 ng.ml-1.h. For a low fluid load the corresponding values at acidic vs alkaline pH were half-life 10.1 vs 16.0 h; Ae 15.9 vs 2.6 mg; CLR 267 vs 33 ml.min-1; AUC 1045 vs 1540 ng.ml-1.h. It is concluded that urinary pH affects flecainide pharmacokinetics independently of urinary flow rate, and that a high flow enhances the elimination of flecainide only with an alkaline urine. This effect of flow rate does not appear to be of clinical relevance.

Ammonium Chloride↗
PubMed1990

Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations.

European data on the polymorphic metabolism of debrisoquine, sparteine, dextromethorphan and mephenytoin have been collected. No significant difference in phenotype frequencies was found between the separate series for debrisoquine, sparteine and dextromethorphan, which supports the claim that these probe drugs reflect the same enzyme polymorphism. The mean frequency of the phenotype slow debrisoquine metaboliser was 7.65% based on 5005 determinations. The overall mean reflecting all three drugs and 8764 determinations was 7.40%. This is consistent with a gene frequency of 0.27 (95% confidence interval 0.26-0.28). The overall mean of the phenotype slow metaboliser of mephenytoin was 3.52% corresponding to a gene frequency of 0.19 (confidence interval 0.17-0.20). The incidence of slow metabolism of debrisoquine and possibly also of S-mephenytoin was homogeneous in the samples from European populations. This is of considerable interest as interethnic differences are now being found both in the phenotypic characters as well as the genotypes of polymorphic drug oxidation.

Debrisoquin↗
PubMed1990

[Double blind biometric study on postoperative effects of analgesics].

A double blind trial to study the effects of analgetics was carried out in patients suffering from pain after third molar osteotomy. 204 patients were evaluated after random allocation to treatment with paracetamol 500 mg and paracetamol 500 mg plus codeine 30 mg. Statistical evaluation revealed a tendency for better analgesia using the combination of paracetamol and codeine. For further studies an exact stratification for sex and age is necessary. Sample sizes of 150 patients are necessary for each parameter.

Acetaminophen↗
PubMed1989

Relevance of genetic polymorphism in drug metabolism in the development of new drugs.

Drugs whose principal metabolic pathways are under polymorphic genetic regulation may show considerable interindividual pharmacokinetic variability. This could lead to clinically significant differences in the pharmacological responses of some patients and so might lead the pharmaceutical industry to stop development of the drug. This can be prevented and there are several measures that can be taken to avoid such premature termination of development. They include studies in vitro with human liver samples, and clinical pharmacological experiments designed specifically to examine possible genetic polymorphism in the disposition of the drug.

Animals↗
PubMed1989

The role of clinical trials in drug regulation.

Clinical trials and the judgement of the appropriateness of the clinical outcomes are of paramount importance in the process of the evaluation procedure before marketing authorization. Even if the mode of action of the drug remains to be elucidated, the outcome of properly designed and well-performed clinical trials will override this drawback if the results are in favor of the new drug. The critical issue from the medical point of view is the appropriateness of the outcome as "predictor" in terms of therapeutic efficacy. The relationship between pharmacologic effects and the therapeutic efficacy is often a matter of concern, particularly in short-term trials with drugs intended for long-term use and prophylactic indications. In conclusion, despite controversies on their value, clinical trials remain the cornerstone in drug evaluation as a scientific basis for drug regulation.

Cohort Effect↗
PubMed1989

The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide.

The pharmacokinetics and urinary excretion of flecainide (50 mg administered orally) were investigated in five extensive metabolizers (EMs) and five poor metabolizers (PMs) of the sparteine/debrisoquin type of polymorphism under conditions of controlled urinary pH. Flecainide disposition was altered in the PMs. The AUC was higher (1462 +/- 407 versus 860 +/- 256 hr ng/ml), the elimination half-life prolonged (11.8 versus 6.8 hours), and the amount excreted in the urine was higher (26.7 +/- 7.2 versus 15.4 +/- 1.3 mg) in PMs compared with EMs (p less than 0.05). Oral clearance of flecainide was reduced (p less than 0.019) in PMs (600 +/- 139 versus 1041 +/- 307 ml/min in EMs). The renal clearance was similar (p greater than 0.05) in PMs (308 +/- 70 ml/min) and EMs (315 +/- 69 ml/min) and, consequently, PMs had a lower (p less than 0.008) metabolic clearance of flecainide (292 +/- 136 versus 726 +/- 240 ml/min in EMs). Under conditions of uncontrolled urinary flow and pH, renal excretion of flecainide will be reduced and the difference in disposition will be greater. In PMs with renal impairment, accumulation of flecainide to very high serum concentrations may be anticipated, and this may result in proarrhythmic effects.

Adult↗
PubMed1989

Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.

1. The disposition of the enantiomers of the antiarrhythmic drug flecainide has been studied in five extensive (EM) and five poor (PM) metabolisers of sparteine/debrisoquine after administration of 50 mg of racemic flecainide acetate under conditions of high urinary flow rate and acidic urinary pH. 2. In the EM subjects there were no significant differences in the oral clearance, half-life or urinary excretion of (+)-S- and (-)-R-flecainide. 3. In the PM subjects differences in the pharmacokinetics of S- and R-flecainide were observed. The oral clearance of R-flecainide (467 +/- 109 ml min-1) was less (P less than 0.03) than that of the S-enantiomer (620 +/- 172 ml min-1). The half-life of R-flecainide (12.9 h) was longer (P less than 0.03) than that of S-flecainide (9.8 h). The renal clearance of the two enantiomers was, however, comparable and similar to that observed in the EM subjects. The urinary recovery of R-flecainide (15.6 +/- 3.7 mg) was greater (P less than 0.03) than that of the S-enantiomer (12.0 +/- 3.7 mg). The enantioselective disposition observed in PMs is therefore due to greater impairment in the metabolism of R- than S-flecainide. 4. The urinary recoveries of two major metabolites of flecainide, meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) were lower (P less than 0.05) in PMs, 12.0% +/- 3.1% and 8.2% +/- 3.2% of the dose administered, respectively, than in EMs of 17.7% +/- 3.3% and 16.5% +/- 3.3%, respectively. 5. One PM subject had a greatly diminished flecainide metabolic capacity and a rare genotype, as assigned by Xbal RFLP analysis.

Debrisoquin↗
PubMed1989

Plasma clearance of bile acids in the rat: hepatic uptake under physiological conditions without countertransport.

Studies in rats by others indicated that sulfobromophthalein (BSP), bilirubin and indocyanine green are taken up by the liver and can be transported back to plasma against the prevailing concentration gradient (= countertransport). The present in vivo study was designed to determine whether the bile acids cholic acid and taurocholic acid under physiological conditions undergo appreciable countertransport as has been suggested by experiments in isolated hepatocytes. Experiments with BSP (controls) showed that injections of unlabeled BSP into rats five minutes after the administration of radiolabeled BSP was followed by a release of radioactivity into plasma (BSP-countertransport). In contrast bile acid countertransport could not be demonstrated, no matter whether it was tested 1, 5 or 8 minutes after the administration of radiolabeled cholic- or taurocholic acid.

Animals↗
PubMed1987

Absence of a clinically significant interaction between theophylline and furosemide.

In new of previous contradictory results, the possible interaction between the loop diuretic furosemide and theophylline was re-evaluated in 12 healthy volunteers with a steady-state plasma theophylline level. Two doses of furosemide 20 mg at a 4 h interval did not influence the steady-state plasma concentration of theophylline despite causing a moderate diuresis. Urinary recovery of theophylline and its metabolites amounted to 106 +/- 21% of the dose without furosemide and 96 +/- 19% of the dose with furosemide, demonstrating that there was no influence on the enteral absorption of theophylline of the furosemide treatment. After the first dose of furosemide the fractional renal clearance (CLR1) of theophylline (fractional = hourly sampling period) changed in parallel with the urinary flow rate, without a significant difference between treatment with and without furosemide. After the second dose of furosemide, CLR1 was increased in the first hour and then it declined to levels far lower than the control value. This unexpected result could explain the unchanged plasma concentration of theophylline during furosemide treatment.

Adult↗
PubMed1987

Enoxacin--a potent inhibitor of theophylline metabolism.

The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.

Adult↗
PubMed1987

Influence of theophylline on the renal clearance of erythromycin.

The influence of theophylline on the kinetics of erythromycin was studied in 11 healthy subjects who received both drugs intravenously in therapeutic doses. Total clearance, terminal half-life and volume of distribution of erythromycin were not altered by concomitant theophylline treatment. However, renal clearance of erythromycin was enhanced by theophylline treatment (86.0 +/- 81.1 ml/min vs. 32.5 +/- 15.9 ml/min, with vs. without theophylline). Theophylline also altered urinary flow rate (4.7 +/- 1.6 ml/min vs. 1.9 +/- 1.2 ml/min, with vs. without theophylline) whereas fluid intake was identical (125 ml/h) as well as the pH of the urine (pH 6.5). The possible explanation that theophylline is acting via enhancing urinary flow rate, which reduced tubular reabsorption of erythromycin, has been ruled out by the findings of an additional trial done in 6 out of the 11 subjects. In this trial, renal clearance of erythromycin was not influenced by enhanced urinary flow rate (7.2 +/- 1.9 ml/min) which was due to high fluid intake (500 ml/h) whereas the pH of the urine was kept at 6.5 as in the first part of the study. When other mechanisms to explain the observed interaction were discussed taking into account our published results on theophylline kinetics influenced by concomitant erythromycin administration, the most likely explanation for our finding seems to be the interaction between erythromycin and 1-methyluric acid, one of the theophylline metabolites.

Adult↗
PubMed1986

Pharmacokinetics of erythromycin in patients with different degrees of renal impairment.

The kinetics of erythromycin (E.) was studied in 16 patients with different degrees of impairment of renal function after a single intravenous dose. Renal clearance of E. was found to be significantly correlated to the creatinine clearance. Total recovery in urine did not exceed 7.5%. As expected from the small fraction excreted via the kidneys, the elimination half-life and the total clearance of E. did not depend on renal function. We conclude that impairment of renal function does not justify a dose adjustment of E. Hearing acuity should, however, be monitored during treatment since transient deafness predominantly in patients with renal failure has been reported by various authors.

Adult↗
PubMed1985

Integrated pharmacokinetics and pharmacodynamics of atropine in healthy humans. I: Pharmacokinetics.

The pharmacokinetics of atropine in three healthy male volunteers after intravenous administration of 1.35 and 2.15 mg of the drug was determined. Pharmacodynamic effects of atropine were measured simultaneously. All the data were fitted to a novel integrated kinetic-dynamic model. Plasma concentrations of atropine and the amounts of atropine and its primary metabolite, tropine, excreted in the urine were measured by a sensitive gas chromatographic-mass spectrometric assay. The kinetics of elimination of atropine was first order. There was evidence that the kinetics of distribution of the drug was dose dependent. Two phases with apparent half-lives of 1 and 140 min were distinguishable in accordance with a linear two-compartment disposition model for atropine. The urinary excretion of unchanged drug was 57% of the dose. The steady-state volume of distribution was 210 L, implying extensive tissue binding and/or partitioning. Renal plasma clearance was 660 mL/min, suggesting significant tubular secretion. The renal clearance of atropine depended on urine flow. Urinary excretion of tropine amounted to 29% of the dose. The kinetics of the metabolite was first order.

Adult↗