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Biomedical subjects

T W Guentert

Publications and source records attributed to T W Guentert.

68 records · Page 4Linked to original sources
PubMed1980

Gastrointestinal absorption of quinidine from some solutions and commercial tablets.

The gastrointestinal absorption of quinidine from three commercially available tablet products has been compared to that from a quinidine sulfate solution previously found to have 70% of the systematic availability of an intravenous dose. Quinidine gluconate solution was included in the study to compare the absorption characteristics of the two quinidine salts. The tablets were given in a counterbalanced sequence preceded by one quinidine solution and followed by the other in a crossover design. The three tablets proved to be equivalent to one another with respect to extent and rate of absorption. The absorption properties of the two solutions were indistinguishable. The tablets were equivalent to the solutions in extent but not in rate of absorption.

Adult↗
PubMed1980

Evaluation of the absorption from some commercial sustained-release theophylline products.

Absorption of theophylline from three commerical products labeled as sustained release was compared to the absorption from a standard uncoated tablet (Searle 200-mg aminophylline tablet) in a single-dose study. Aminodur tablets (Cooper) and Slophyllin Gyrocap capsules (Dooner) had bioavailability (100.2% +/- 19.8% and 98.5% +/- 13.8%) statistically indistinguishable from that of the standard but showed significantly slower absorption (peak times of 10.4 +/- 2.8 and 4.36 +/- 1.35 hr) and lower peak plasma concentrations (13.9 +/- 4.5 and 22.6 +/- 3.5 micrograms/ml/g dose) than the standard (tpeak, 1.52 +/- 0.45 hr; Cpeak, 28.1 +/- 6.2 micrograms/ml/g dose). The time of the plasma concentration peak (2.47 +/- 1.38 hr) after a dose of Tedral S.A. (Warner/Chilcott) was not statistically different from that after the standard, but both the peak concentration (16.0 +/- 3.9 micrograms/ml/g dose) and availability (76.0 +/- 18.4%) were. Multiple-dose projections from single-dose data indicate that of the three test products only Aminodur maintains reasonably constant interdose plasma levels during 12 hoursly dosing. With an 8 hourly dosing schedule Gyrocaps also might be satisfactory. Reasonable predictions of the plasma concentrations arising from Aminodur doses have been made using a single-compartment body model and assuming input from an outer followed by an inner layer of the tablet.

Biological Availability↗
PubMed1980

Evaluation of the absorption from some commercial enteric-release theophylline products.

In a single-dose bioavailability study, Wales, Robinson, Columbia, and Choledyl (Warner/Chilcott) enteric-coated tablets all allowed a bioavailability of theophylline (99% +/- 25%, 102% +/- 23%, 103% +/- 18%, and 98% +/- 15%; mean +/- SD, n = 12) statistically indistinguishable from that of the standard uncoated tablet (Searle 200 mg aminophylline). Only the Wales and Choledyl tablets (7.6, 4.2 hr) could be shown (p < 0.5) to generate a peak plasma theophylline concentration later than the standard (1.4 hr). All tablet brands demonstrated a significant lag time before appearance of theophylline in the plasma, and both Wales and Choledyl tablets also had a (tpeak-tlag) statistically different from that of the standard. Despite misleading indications from the mean plasma profile (plasma concentrations at each sampling time averaged over all subjects), plasma data from the individual participants and in vitro dissolution data show that, while release of theophylline from the Wales tablet might be inordinately slow, this is not a sustained-release preparation. Of the enteric-coated tablets only the Columbia product allowed significant levels in the first sample after dosage. Five of the 18 Columbia doses gave rise to 40-99% of the peak concentration in the 1-hr sample. In vitro, it takes 39 +/- 14 min for 40% of the theophylline content of Columbia tablets to dissolve in simulated intestinal fluid. Suprisingly rapid delivery of an enteric-coated tablet to the duodenum would appear to be required to allow a significant percentage of theophylline to be dissolved and absorbed before 1 hr. None of 12 Columbia tablets tested in vitro, however, allowed dissolution of more than 1.2% of their theophylline content during 1 hr immersion in simulated gastric fluid. Since once in intestinal fluid Columbia tablets appear to dissolve more rapidly than the other enteric products, it is not clear whether the five Columbia tablets in question had imperfections or wheter, in fact, this tablet brand more closely than the others represents the ideal of immediate release once in the duodenum. Plasma samples should be taken as early as 15 min after dosage when evaluating the bioavailability of enteric release products.

Adult↗
PubMed1980

Effect of saturable binding on the pharmacokinetics of drugs: a simulation.

The time-courses of both total and unbound drug concentrations with time were simulated under conditions of saturable binding to either plasma proteins or tissues, or both, following a single intravenous dose. The curves were either linear, convex, or concave, depending upon the extent of distribution and the intrinsic ability of an eliminating organ to remove drug from the body. Saturable binding should therefore be considered whenever data showing nonlinear semilogarithmic decline are to be interpreted.

Blood Proteins↗
PubMed1980

Effect of plasma protein binding on quinidine kinetics in the rabbit.

The relationship between the unbound fraction and kinetic parameters describing the disposition of quinidine in rabbits with a wide spread in protein binding values was examined. Both total and unbound quinidine concentrations followed two-compartment kinetics. The blood clearance of unbound quinidine, as well as the apparent volumes of distribution for both total and unbound quinidine, were correlated with the unbound fraction of the drug in plasma. No correlations were observed between the unbound fraction and the clearance of total quinidine or the fast and slow disposition rate constants of free and total drug. These observations are in agreement with the proposed models for elimination of drugs by the liver. They suggest, however, an interrelationship between binding to plasma proteins and binding to other proteins which is not taken into consideration in accepted models for apparent volume of distribution. Because unbound drug is the pharmacologically active species and clearance of unbound drug is the main determinant of unbound steady-state plasma concentrations, the measurement of protein binding of drugs with a high extraction ratio in the eliminating organ is essential for drugs with a narrow therapeutic index.

Animals↗
PubMed1979

Evaluation of a modified high-performance liquid chromatography assay for acebutolol and its major metabolite.

Extensive modification of an existing high-performance liquid chromatography assay for acebutolol and its major metabolite has markedly improved chromatographic stability eliminating the previous need for frequent adjustment of the eluent composition to accommodate continuous loss of column retention. The eluents now used and avoidance of the requirement for elevated column temperature may be significant factors in the ability to maintain column life over 8 months of continuous use with little decrease in retention. As a result of the improved chromatographic stability full advantage can now be taken of automatic injection devices for the unattended processing of large numbers of samples. A significant modification of the work-up of blood samples has improved precision of the assay in whole blood. Nevertheless, it is recommended that plasma samples rather than whole blood be analyzed, since the plasma assay is faster and still more precise.

Acebutolol↗
PubMed1979

Determination of quinidine and metabolites in urine by reverse-phase high-pressure liquid chromatography.

A new reverse-phase high-pressure liquid chromatography assay allowing simultaneous but separate quantitation of urinary levels of quinidine and its major metabolites, 2'-quinidinone, 3-OH-quinidine and a newly detected N-oxide, is described. The compounds were separated on a alkyl phenyl column using 0.05 M phosphate buffer pH 4.5/acetonitrile/tetrahydrofuran (80 : 15 : 5, v/v) as mobile phase and were detected by UV at lambda = 230 nm. The assay procedure includes extraction of the compounds from urine samples into a mixture of dichloromethane/isopropanol (4 : 1, v/v), evaporation of the organic extracts to dryness and reconstitution of the residue in acetonitrile. The new assay was compared to a modification of the Cramer and Isaksson fluorescence assay which has recently been recommended for analysis of quinidine in urine. The consistently higher quinidine levels observed in the fluorescence assay could be accounted for by the quinidine levels and metabolite carry-over as determined by HPLC.

Chromatography, High Pressure Liquid↗
PubMed1979

Determination of quinidine and its major metabolites by high-performance liquid chromatography.

A specific and precise assay, capable of quantitating in human plasma simultaneously but separately quinidine, dihydroquinidine and the quinidine metabolites 2'-quinidinone, 3-OH-quinidine and a third metabolite found--tentatively identified as the product formed by rearrangement of quinidine-N-oxide-is reported. The assay uses a normal phase high-performance liquid chromatographic (HPLC) system with a variable-wavelength UV detector at 235 nm and has a limit of sensitivity at approximately 20 ng/ml. The mobile phase consists of hexanes-ethanol-ethanolamine (91.5:8.47:0.03). A 2-ml plasma sample is worked up by adding primaquine base as an internal standard and extracting with ether-dichlormethane-isopropanol (6:4:1). The organic extract is evaporated and the residue reconstituted in 100-600 micron1 of mobile phase and an aliquot injected onto the column. Comparison of this procedure with the Edgar and Sokolow (dichloroethane) extraction--fluorescence procedure and with the Cramer and Isaksson (benzene) double extraction--fluorescence assay indicates that both fluorescence procedures give quinidine concentrations up to 2.3 times those determined by HPLC. These discrepancies were shown to be due to carry-over of metabolites and some extraneous background fluorescence.

Chromatography, High Pressure Liquid↗
PubMed1979

Divergence in pharmacokinetic parameters of quinidine obtained by specific and nonspecific assay methods.

Previously published estimates of pharmacokinetic characteristics of quinidine can be shown to be dependent on whether the investigators have used analytical methods which are specific for quinidine. Areas under the plasma concentration-time curve and peak plasma concentrations after administration of the drug were higher and clearance values consequently lower in studies utilizing nonspecific assays unable to distinguish quinidine from its metabolities. The error introduced is larger after oral administration as a result of marked first-pass metabolism of quinidine. The absolute oral bioavailabilities from pharmaceutical preparations might therefore be estimated higher in studies with assays including metabolites in the determination. Although the pharmacodynamic response to quinidine is related to the plasma concentration, the therapeutic window of drug concentrations has been defined only using nonspecific assays. In light of the availability of newly developed specific assays, redefinition of the range of therapeutic plasma concentrations is opportune.

Biological Availability↗
PubMed1979

Quinidine pharmacokinetics in man: choice of a disposition model and absolute bioavailability studies.

Parameters describing disposition and absolute oral bioavailability of quinidine were determined in ten normal male volunteers using a specific assay. Various models were compared for their ability to describe the experimental data. An intravenous quinidine gluconate and an oral quinidine sulfate solution were administered (3.74 mg/kg quinidine base). In three subjects the intravenous and oral studies were repeated. One-, two-, and three-compartment models with zero and first-order input were fitted to the plasma concentrations. The selection of the best model was made by the Akaike information criterion and by eye. After intravenous administration, plasma concentration-time curves could be adequately described by a two-compartment model. Mean disposition constants (+/- SD) were obtained from individualized fits (V1: 0.398 +/- 0.336 LITER/KG, Vdarea: 2.53 +/- 0.72 liter/kg, alpha: 0.316 +/- 0.294 min -1, beta: 0.00204 +/- 0.00262 min -1, k2: 0.0305 +/- 0.0101 min -1). A clearance of 4.9 +/- 1.5 ml/min/kg was observed. After oral administration, three-compartment models were needed to describe the observed data in some cases. Absorption was in most cases best described by a zero-order rather than by a first-order process. The time to peak concentration varied from 23 to 121 min, the lag time was always less than 3 min, and the mean elimination rate constant was 0.00171 min -1. The mean oral bioavailability of quinidine was 0.70 +/- 0.17.

Administration, Oral↗
PubMedDate not supplied

Isolation, characterisation and synthesis of a new quinidine metabolite.

In addition to the well-known quinidine metabolites, 2'-quinidinone and 3-hydroxy-quinidine, a third metabolic product was detected in the plasma of cardiac patients receiving quinidine therapy. Mass spectroscopic, 13C- and 1H-NMR studies, together with information on UV and IR properties of the isolated and also synthetically accessible compound, suggested the presence of an aliphatic N-oxide group. The structure of quinidine-N-oxide for the hitherto unknown metabolite was finally confirmed by X-ray diffraction analysis. Evidence was found to indicate that a contaminant in quinidine preparations, dihydroquinidine, is metabolized with respect to N-oxidation in the same way as quinidine.

Biotransformation↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of quinidine and its metabolite, quinidine-N-oxide, in beagle dogs.

Quinidine and one of its major metabolites, quinidine-N-oxide, were given by separate i.v. infusions to each of three beagle dogs. Plasma and urine samples were analysed for pharmacokinetic comparison of the drug and its metabolite. Quinidine apparently distributed into two major compartments, while the N-oxide distributed into three compartments. The compartment-independent pharmacokinetic parameters (mean +/- SD) were for quinidine Vdss 4.78 +/- 1.11 l/kg, clearance 0.074 +/- 0.047 l/min, terminal half-life 720 +/- 343 min and for quinidine-N-oxide Vdss 1.03 +/- 0.21 l/kg, clearance 0.065 +/- 0.012 l/min, terminal half-life 316 +/- 69 min. Only 29% of quinidine was recovered in the urine as unchanged drug while 77% of the N-oxide was excreted unchanged via the kidney. Non-linear renal elimination of the N-oxide was observed in two out of three dogs with a Michaelis-Menten constant, KM of about 7 micrograms/ml (21 microM). Prolongation of the QT-interval in the ECG response was used for comparing pharmacodynamic effects. Quinidine was about three to four fold more active than the N-oxide at similar plasma concentrations. Quinidine-N-oxide concentrations in plasma after quinidine administration were very low and would not contribute significantly to the quinidine effect.

Animals↗
PubMedDate not supplied

Time-dependence in benzodiazepine pharmacokinetics. Mechanisms and clinical significance.

Several studies investigating changes with time in pharmacokinetic parameters of several benzodiazepines are reviewed. At least 3 possibilities (enzyme induction, enzyme inhibition by metabolic products, and unchanged kinetics following long term therapy or high doses) have been postulated in the disposition processes of diazepam. It seems likely that the contradictory results which have been reported can be explained by differences in 1 or several experimental factors influencing the outcome of a study (patient compliance, multiple drug therapy or statistical design). With the 3-hydroxybenzodiazepine lorazepam and the nitro-benzodiazepine nitrazepam, no changes in metabolic activity were observed. Studies with clonazepam in monkeys have confirmed previous observations that reduced metabolic activity during periods of physical inactivity gives rise to circadian fluctuations in steady-state concentrations of the drug. Furthermore, systemic and intrinsic clearances of midazolam were found to be higher following an intravenous dose in the late afternoon than after a morning dose. The protein binding of diazepam is also subject to diurnal variations, and concomitant changes in apparent volume of distribution and clearance have been observed. From the existing data it seems likely that the rate of absorption of several benzodiazepines (including diazepam, clobazam and clorazepate) varies periodically with a 24-hour cycle, pointing to diurnal effects on drug absorption processes.

Anti-Anxiety Agents↗