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Biomedical subjects

P H Hinderling

Publications and source records attributed to P H Hinderling.

15 recordsLinked to original sources
PubMed1991

Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans.

Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean +/- SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 +/- 2.0% and feces 17.1 +/- 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 +/- 3.0%, dihydrodigoxin 2.8 +/- 1.6%, digoxigenin bisdigitoxoside 1.6 +/- 0.1%, and additional metabolites 1.5 +/- 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 +/- 25 ml min-1 and 152 +/- 24 ml min-1. The mean steady state volume of distribution was 489 +/- 73 L and the mean residence time 41 +/- 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 +/- 9 h and 53 +/- 11 h; the renal clearances were 79 +/- 13 ml min-1 and 100 +/- 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 +/- 1.98% and feces 31.6 +/- 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 +/- 11.4%, dihydrodigoxin 4.5 +/- 3.9%, digoxigenin bisdigitoxoside 1.9 +/- 0.1%, polar metabolites 5.5 +/- 3.8%, and additional metabolites 1.3 +/- 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 +/- 2.5 ng ml-1 and 9.5 +/- 1.1 ng ml-1 for digoxin were observed at 40 +/- 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 +/- 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 +/- 28 ml min-1 and 37 +/- 4 h after p.o. administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1989

[Developments in drugs and populations at risk].

No therapeutic effectiveness without unwanted side-effects. This well-known problem persists in spite of modern methods for development of new drugs. Therefore no drug-therapy should be initiated without exact risk-benefit-analysis. Especially for drugs introduced recently, effectiveness is better defined than tolerance. In the USA annual costs of 3 million $ due to drug-side-effects have been estimated, indicating an immense socio-economic relevance next to medical or personal aspects. Therefore effective means and strategies should be accepted and used: General reduction of drug consumption, avoidance of polytherapy with respect to known and unknown interaction of side-effects, strict observation of proper indications, amelioration of surveillance for recently introduced drugs and better consideration of special populations at risk.

Consumer Product Safety↗
PubMed1988

Detection of populations at risk and problem drugs during drug development and in pharmacotherapy.

Rational drug therapy requires knowledge about the ratio of risk (adverse drug reaction) to benefit (therapeutic efficacy) for all drugs to be used in humans. However, with newly marketed drugs, the risk/benefit ratio is usually not sufficiently known. Safety is often less well defined than efficacy. This is the result of the present mode of drug development. Premarketing studies are conducted in comparatively small, homogenous populations over relatively short time intervals and under standardized conditions. Only after marketing are larger, more diversified populations exposed over prolonged times, often under uncontrolled conditions. Adverse drug reactions (ADRs) are the result of either overdosage, or allergic or idiosyncratic reactions. They can be life-threatening or mild. Some of the ADRs are common (greater than 1:10); others are very rare (less than 1:1000). The overall rate of ADR occurrence in ambulatory and hospitalized patients is high enough to have significant socioeconomic consequences. Some of the risk populations can be suspected a priori: elderly, multimorbid patients and patients with compromised drug elimination who may be overdosed if the regimens are not appropriately modified. Some problem drugs may be recognized if they display one or more of the following characteristics: narrow therapeutic index, steep dose-effect relationship, nonlinear kinetics, variable bioavailability, and pharmacogenetically determined kinetics. Other individuals at risk, however, may not be readily identifiable. They develop allergic and idiosyncratic reactions after drug exposure without exhibiting easily recognizable predisposing factors. In order to determine the number of individuals so affected, and the associated drugs as quickly as possible during the developmental process, specific ADR surveillance measures are taken.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Hypersensitivity↗
PubMed1988

Integrated plasma and synovial fluid pharmacokinetics of tenoxicam in patients with rheumatoid arthritis and osteoarthritis: factors determining the synovial fluid/plasma distribution ratio.

Single oral doses of 40 mg of the nonsteroidal antiinflammatory drug, tenoxicam, were given to four patients (three with rheumatoid arthritis, one with osteoarthritis). The concentrations of the drug in synovial fluid and plasma were measured by a specific high-performance liquid chromatography method. The unbound fractions of the drug in both fluids were determined at pH 7.4 and 37 degrees C by equilibrium dialysis. The possible influence of the pH on the protein binding was also assessed. The total concentration time curves in plasma and synovial fluid were fitted to linear oral 1 and 2 compartment body models with an additional synovial fluid compartment connected to the central compartment. The unbound fractions of drug in synovial fluid and plasma were on average 0.015 and 0.011, respectively: not significantly different from each other. The protein binding of tenoxicam was pH dependent with increased free fractions at pH values less than 7.4. The average peak concentrations of tenoxicam in plasma and synovial fluid were 4.3 and 1.4 micrograms/ml, respectively. The mean ratio of the areas under the total concentration time curves in synovial fluid and plasma was 0.42, which corresponded to the steady state of equilibrium ratio of the total drug concentrations in the two body fluids. Two hypotheses were tested: hypothesis I assuming that equilibration across the synovial tissue takes place between the unbound, unionized tenoxicam molecules; hypothesis II assuming that equilibration across the synovial tissue is established between the unbound (unionized + ionized) tenoxicam molecules. Based on the available evidence hypothesis II was rejected.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Comparative evaluation of equilibrium dialysis methods employing biological and artificial membranes for the determination of protein binding of drugs.

The goal of the study was to investigate comparatively the performance of the conventional equilibrium dialysis method using artificial membranes (AED) and an alternative equilibrium dialysis method employing biological membranes of red blood cells (BED). The following criteria were employed for an assessment of the two methods: (a) mean estimate of the fraction of drug unbound in plasma, (b) precision, and (c) time required for establishing equilibrium dialysis. For this purpose, plasma protein binding data by AED and BED obtained for several compounds in our laboratory were employed. In addition, suitable results of further compounds on the plasma protein binding by AED and on the partitioning in red cell buffer and plasma systems were collected from the literature, allowing a calculation of the plasma protein binding by BED. Plasma protein binding values by AED and BED were available for a total of 22 nonelectrolytic and electrolytic compounds, including the entire possible range of binding values. Plots of the mean plasma unbound fractions as obtained by AED and BED for the compounds studied could be fitted by a straight line with slope and intercept not significantly different from unity and zero, respectively. Also, the precision of the two methods appeared to be similar. However, the times required to reach equilibrium dialysis were significantly different: With BED and AED, this time span ranged between 2 and 45 and 180 and 960 min, respectively. These results indicate that overall the BED method offers a significant advantage over the AED procedure: It is less time consuming and hence possibly more reliable.

Blood Proteins↗
PubMed1986

Comparative in vivo evaluation of a radioimmunoassay and a chromatographic assay for the measurement of digoxin in biological fluids.

The concentrations of digoxin in plasma and urine samples obtained from three healthy male volunteers, who received 1.2 mg of labeled digoxin perorally and intravenously, were simultaneously measured by a commercially available radioimmunoassay (RIA) and by a combined column thin-layer chromatographic assay (CA). The CA method, previously shown to assay digoxin specifically, was also used to monitor the individual digoxin metabolites. The results of this investigation showed that digoxin was significantly metabolized, particularly after peroral administration. The lower level of sensitivity of the RIA in plasma was 0.4 ng/mL. There were highly significant positive linear correlations between the values of the following parameters of digoxin as obtained by the RIA and CA methods: the concentrations in plasma and urine, the AUCs, and the cumulatively excreted amounts in urine. The two assays did not give completely identical results either with plasma or urine; the slopes of the regression lines deviated from unity in a significant number of cases. However, there was no relationship between the magnitude of the slopes of the regression lines and the extent of metabolism. It was concluded that the commercially available RIA evaluated was specific for digoxin and that the presence of digoxin metabolites did not affect the determinations.

Biotransformation↗
PubMed1978

Significance of the pharmacokinetics of antimicrobial drugs.

Administration of an active drug to the intact human body leads to a "drug-body" interaction: the drug exerts its effect on the body, the body disposes of the drug. Administration of an antimicrobial drug to a human body infected with pathogenic bacteria leads to a "drug-bacteria" interaction in addition to "drug-body" and "bacteria-body" interactions. Of these complex interacting mechanisms only the disposition effect of the human body on antibacterial drugs and the effect of antimicrobial agents on bacteria have been quantified, analyzed, and are thus predictable. Postulates have been derived from the findings of these studies and have given the rationale for proper antimicrobial therapy under clinical conditions: antimicrobial actions are functions of the duration and concentration of the active antimicrobial principle at the physiological site of action. Optimal therapeutic efforts consider the need for individual treatment with respect to the choice and type of dosage regimen of the antimicrobial agent administered.

Acetylation↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans I: intravenous studies.

The pharmacokinetics of intravenously administered solutions of 0.30-and 0.60-mg bolus doses of 3H-beta-methyldigoxin, labeled in the 12alpha-position, were dose independent. Individual radioactivities assignable to the parent drug and specifically identified metabolites after TLC separation were followed in the plasma, urine, and feces. A sum of four exponentials described the plasma beta-methyldigoxin data with apparent half-lives of 0.04, 0.33, 3.5, and 41 hr. beta-Methyldigoxin was 10% plasma protein bound and had a red blood cell-plasma water partition coefficient of 0.9. The only significant metabolite observed in plasma was digoxin, although glucuronides and sulfates of beta-methyldigoxin, digoxin and digoxigenin also were observed in urine. As much as 92 +/- 3% of the dose was excreted by all processes by 144 hr. Of this amount, renal excretion accounted for fractions that were 0.47 unchanged, 0.35 digoxin, and 0.058 water-soluble metabolites. The fraction in the feces was 0.13. The urine flow independent renal clearances of beta-methyldigoxin and derived digoxin were 59 and 206 ml/min, respectively. The metabolism was a relatively fast process. The terminal pseudo-steady-state elimination of beta-methyldigoxin with a half-life of 41 hr was reached 27 hr after drug administration and was primarily dependent on the slow release of sequestered or distributed drug drom the tissues into the central compartment. The drug and metabolite levels in plasma and urine were consistent with analog computer fitting to the proposed pharmacokinetic multicompartmental model.

Adult↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans II: Oral studies and bioavailability.

The pharmacokinetics of orally administered aqueous 3H-beta-methyldigoxin solutions were studied at two dose levels, 0.3 and 0.6 mg, in healthy human subjects. The drug and its metabolites were specifically assayed in biological fluids and compared with results after intravenous doses to the same subjects. No significant dose dependency was observed. The apparent half-life of absorption was 16+/-6 min (SEM). Digoxin was the only metabolite observed in the plasma and comprised 28.6+/-3.7% of the dose in the urine. 3H-beta-Methyldigoxin, renally excreted unchanged, comprised 25.7+/-1.7% (SEM). Water-soluble metabolites in the urine comprised 9.0+/-1.8%. Fecal and urinary excretion accounted for 85% of the dose at 144 hr. The oral absorption of unchanged 3H-beta-methyldigoxin from solution was 59+/-6% by area under the curve methods and 60+/-4% by renal excretion. A total of 73% of the dose in the solution was absorbed as beta-methyldigoxin and digoxin. First-pass metabolism prior to absorption was largely prehepatic and assignable to GI degradation; 21.9+/-2.8% was degraded with 12.8+/-4.0% to digoxin and 9.1+/-4.0% to water-soluble metabolites. From 14 to 18% of the administered oral dose did not reach the systemic circulation. Analog computer fitting of plasma and urine levels of drug and digoxin was consistent with the first-pass premise with a delayed absorption of GI-generated digoxin and other metabolites. There were no significant differences between the oral absorption of a tablet formulation and the solution. Orally administered beta-methyldigoxin solution delivered 97% cardioactivity as itself and digoxin with respect to an equivalent amount of intravenously administered digoxin. This value contrasts to the 140% delivered by intravenously administered beta-methyldigoxin on the premise of pharmacodynamic equivalence of systemically appearing digoxin and beta-methyl-digoxin. Literature reports on the oral bioavailability of solutions and solid dosage forms of digoxin were critically reviewed, but no reliable comparison of the extent and reproducibility of oral absorption of cardioactive agents from administered digoxin or beta-methyldigoxin could be made from the widely variable digoxin studies with nonspecific assays.

Administration, Oral↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans III: Pharmacodynamic correlations.

Significant decreases in left ventricular ejection time and heart rate were observed after the oral and intravenous administration of beta-methyldigoxin. The time course of this action correlated with the time course of beta-methyldigoxin and its active metabolite, digoxin, in their deepest pharmacokinetic compartments and not with their plasma levels. This pharmacodynamic activity peaked (decrease of 6.3% at 0.6 mg iv and 3.5% at 0.3 mg iv; decrease of 3.8% at 0.6 mg po and 4.5% at 0.3 mg po) at about 10 hr, concomitantly with the amounts of beta-methyldigoxin in its deepest compartment and showed a terminal half-life equivalent to the 41 hr for beta-methyldigoxin. The relative peak heights and area under the ejection time-time curves indicated a linear dose-response relationship on intravenous administration and an effect greater than that reported for larger amounts of digoxin. The time course of heart rate action correlated (8.3 and 12.5% decreases with 0.3 and 0.6 mg iv, respectively; 6.5 and 9.5% decreases with 0.3 and 0.6 mg po, respectively) with the time course of beta-methyldigoxin and its metabolite digoxin in shallower pharmacokinetic compartments (peaks at approximately 80 min intravenously and 135 min orally), and significant effects had disappeared by 10 hr after drug administration. This finding indicated that the biophases differ for ejection time and heart rate action. Mean arterial blood pressure could not be correlated with the time course of drug, although a small consistent decrease (4-8%) was observed from 22 to 72 hr after drug administration.

Digoxin↗
PubMed1977

Comparative studies of the protein binding of digoxin and its metabolites.

The protein binding of Digoxin (D), Dihydrodigoxin (DH), Digoxigenin Bisdigitoxoside (DB) and Digoxigenin Monodigitoxoside (DM) was concentration independent and unaltered by the presence of high concentrations of the analogous compounds. The respective percentage of protein binding for D, DH, DB and DM were 22%, 22%, 23% and 27%.

Adult↗