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Biomedical subjects

T W Guentert

Publications and source records attributed to T W Guentert.

At least 55 records · Page 3Linked to original sources
PubMed1987

Overview on the pharmacokinetics of tenoxicam.

Tenoxicam, a new non-steroidal anti-inflammatory drug (NSAID) with an oxicam structure, is entirely ionised at physiological pH, has minimal lipophilic properties, high plasma protein binding, does not accumulate in fatty tissue and skin and thus has a small volume of distribution. Tenoxicam is rapidly and completely absorbed after oral administration. It is entirely metabolised via oxidation and conjugation pathways before elimination. The extraction ratio in the liver is small resulting in a long elimination half-life with a mean of 72 hours. Since no unchanged drug is found in the bile the low half-life cannot be explained by enterohepatic recirculation of parent compound. The low elimination rate of tenoxicam allows for a once-daily dosage (20 mg) regimen. Following multiple dosing during the first two weeks of therapy tenoxicam reaches steady-state levels within 10-20% of predicted values. Several pharmacokinetic factors help make tenoxicam therapy safe and straightforward: it is completely absorbed when taken orally even with meals or antacids, it penetrates easily into synovial fluid, and is excreted as inactive metabolites. Furthermore, drug disposition is not influenced by age, sex or rheumatic disease and unexpected accumulation is not observed.

Adult↗
PubMed1986

Pharmacokinetics of tenoxicam in patients with impaired renal function.

The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5'OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138 +/- 53 micrograms/ml X h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5'OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5'OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.

Adult↗
PubMed1986

Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration.

During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg-1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min-1 resulted in a short elimination half-life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

Absorption↗
PubMed1986

Acceleration of the elimination of tenoxicam by cholestyramine in the dog.

Two commonly used adsorbents, activated charcoal and cholestyramine, were evaluated in vitro for their ability to adsorb the nonsteroidal anti-inflammatory drug tenoxicam and in vivo for their use in influencing the elimination kinetics of this drug. The Langmuir binding isotherms determined in buffer solutions at pH 7.5 indicated a much greater adsorption capacity of cholestyramine (1.63 g of drug per g of resin) than of charcoal (0.18 g/g of adsorbent) for the acidic drug with a pKa of 5.3. When single i.v. tenoxicam administrations to dogs were followed by multiple p.o. cholestyramine doses the elimination rate of the drug was accelerated drastically. Due to an increased total body clearance (0.65 vs. 0.13 liters/hr), the elimination half-life was reduced from a median base-line value of 31 to 5.4 hr and the mean residence time of drug in the body was decreased from 41 to 7.9 hr. In contrast to cholestyramine, charcoal hardly increased the rate of elimination of tenoxicam over the base-line values determined in the same animals. Inasmuch as these results were similar in all three animals investigated and because the study design precluded an influence of the treatment sequence, it is concluded that cholestyramine efficiently sequesters intestinally secreted tenoxicam and can thereby accelerate drug elimination from the body.

Administration, Oral↗
PubMed1985

Kinetics and electrocardiographic changes after oral 3-OH-quinidine in healthy subjects.

3-OH-quinidine, a major quinidine metabolite, has been reported to have antiarrhythmic activity in animals and is suspected to contribute to the effect of quinidine in man. Four healthy subjects received 3-OH-quinidine in increasing oral doses (35, 100, 300 mg) to achieve serum concentrations in the range of those after quinidine dosing in patients. Blood and urine were collected up to 48 hours and blood pressure, heart rate, and averaged ECG complexes were recorded during 12 hours after dosing. Kinetic analysis revealed differences from published data for the parent drug. Renal clearance was 16 L/hr. The elimination t1/2 was 12.4 hours, substantially longer than that of quinidine. No systematic ECG changes were observed in two subjects with maximum concentrations of 55 and 215 micrograms/L. In the other two subjects who achieved higher maximum concentrations (447 and 918 micrograms/L), there was a significant relationship between the length of the corrected QT interval and the serum concentration of 3-OH-quinidine. These first dynamic results indicate that 3-OH-quinidine exerts effects in man resembling those of quinidine and may contribute to the antiarrhythmic activity of quinidine.

Absorption↗
PubMed1984

Pharmacokinetics of quinidine and three of its metabolites in man.

Disposition parameters of quinidine and three of its metabolism, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9 +/- (SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32 +/- 0.06 mg/L; quinidine N-oxide, 0.28 +/- 0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13 +/- 0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89 +/- 0.50 mg/L; 3-hydroxy quinidine, 0.83 +/- 0.36 mg/L; quinidine N-oxide, 0.40 +/- 0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38 +/- 0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves for both i.v. infusion and multiple oral doses. Mean (+/- SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: Vl, 0.37 +/- 0.09 L/kg; lambda 1, 0.094 +/- 0.009 min-1; lambda 2, 0.0015 +/- 0.0002 min-1; EX2, 0.013 +/- 0.002 min-1; clearance (ClQ), 3.86 +/- 0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (+/- SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant kmf, 0.0012 +/- 0.0005 min-1, volume of distribution, Vm, 0.99 +/- 0.47 L/kg; and elimination rate constant, kmu 0.0030 +/- 0.0002 min-1. Quinidine N-oxide: kmf, 0.00012 +/- 0.00003 min-1; Vm, 0.068 +/- 0.020 L/kg; and kmu, 0.0063 +/- 0.0008 min-1. Quinidine 10,11-dihydrodiol: kmf, 0.0003 +/- 0.0001 min-1; Vm, 0.43 +/- 0.29 L/kg; and kmu, 0.0059 +/- 0.0010 min-1. Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.

Administration, Oral↗
PubMed1984

Single dose pharmacokinetics of mabuterol in man.

The pharmacokinetics of 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butylamino-ethanol hydrochloride (mabuterol), a new bronchodilator in the series of phenyl-ethanolamine derivatives, was investigated in six healthy young male volunteers. Use of tritiated compound allowed characterization of the plasma concentration-time profile of unchanged drug after a single oral dose of 40 micrograms in the form of a drinking solution. Peak concentrations of 96-160 pg/ml were reached between 1.5 and 3.2 h and drug concentrations declined thereafter in a biphasic pattern. Elimination of unchanged drug was slow (t 1/2 beta 20-30 h) due to a low clearance (CL/F 3.0 ml/min/kg) and a large volume of distribution (V beta/F 5.8 l/kg). Absorption of the drug from the gastrointestinal tract was complete and availability of unchanged drug to the systemic circulation could be estimated (F greater than 0.91) using flow model concepts. At peak concentrations mabuterol accounted for only 46% of total radioactivity in plasma but no major conjugated or unconjugated metabolite has been identified. The active tert.-butanol-amino-metabolite was present in negligible amounts (less than 10 pg/ml). The time profile of total radioactivity in plasma closely resembled that reported for structurally related compounds. Excretion of total radioactivity was mainly renal (80% of dose) but the fraction of the dose eliminated unchanged in urine was only 24%. Fecal excretion was low with a cumulative amount recovered over the entire study period of 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1984

Pharmacokinetics of tenoxicam in healthy human volunteers.

Tenoxicam, a thieno-thiazine derivative, belongs to a new chemical class of non-steroidal anti-inflammatory drugs. Single dose kinetics was investigated after intravenous and oral administration to define the disposition and general absorption characteristics of the drug. After intravenous administration of 20 mg tenoxicam to 12 volunteers the time course of the plasma concentrations of unchanged drug followed two-compartment model characteristics. The area under the plasma-concentration time curve in the distribution phase contributed however only 3% or less to the total area. The plasma clearance was low with values ranging from 1.3 to 4.2 ml/min and the volume of distribution Vss was small averaging at 20 to 40% of the total body weight. The median half-life of elimination from the body was found to be 72 hours (range 42 to 100 hours). The disposition was not influenced by sex. Tenoxicam is highly bound to plasma albumin. At pH 7.4 the fraction bound exceeded 99% but was highly dependent on the pH. Plasma protein binding in patients with rheumatic disease was not different from that measured in healthy volunteers. The partitioning of tenoxicam into red blood cells was limited. Erythrocyte concentrations were only 20-30% of the corresponding plasma concentrations. After oral administration of a 20-mg tablet complete and rapid absorption of the drug was observed with maximum plasma levels of 1.7 to 3.6 micrograms/ml reached within 0.5 to 2 hours. Due to the rapid absorption and terminal half-life of the drug its plasma concentration profile after oral administration was very similar to that following intravenous dosing. The pharmacokinetic characteristics of tenoxicam offers a rationale to administer the entire dose in one single portion.

Administration, Oral↗
PubMed1982

Factors influencing the apparent protein binding of quinidine.

Various factors influencing the apparent protein binding of quinidine were examined. Different binding values in rabbit plasma were obtained by equilibrium dialysis techniques employing three commonly used buffers. Binding values comparable to those found by ultrafiltration were achieved after dialysis against isotonic phosphate buffer for approximately 4 hr. Dialysis beyond 8 hr gave an increased free fraction with time. The reported effect of in vitro added heparin on plasma protein binding could be prevented by reducing the final concentration in blood from 20 to 5 U/ml, a concentration still sufficient to prevent clotting of the blood sample. Daily freezing and thawing of plasma samples over 1 week did not alter the binding of quinidine. The samples were stable for at least 2 months at -20 degrees.

Animals↗
PubMed1982

Disposition of quinidine in the rabbit.

Quinidine shows two-compartment characteristics in rabbits with a terminal half-life of 67 min for total drug and 58 min for unbound drug. Statistically, the values are not significantly different from each other (p greater than 0.05). The clearances for total and unbound drug are 52 and 464 ml/min/kg, respectively, and the total and unbound apparent volumes of distribution at steady state are 4.2 and 27.3 liters/kg, respectively. The unbound clearance and unbound apparent volume of distribution were inversely related to the unbound fraction of quinidine in plasma. The total clearance and apparent volume of distribution showed no relationship to the binding. Approximately 0.5% of the dose was excreted as unchanged quinidine. Six identifiable metabolites were found in the urine, accounting for approximately 14% of the dose. Two unknown metabolites were also observed in the urine. With the exception of 2'-quinidinone, these metabolites were formed in the rate-limiting step in the metabolite kinetics. The quinidine unbound fraction ranged from 0.06 to 0.23 in the eight rabbits studied. The binding of the metabolites was less pronounced, and only 3-hydroxyquinidine showed a significant correlation with quinidine binding.

Animals↗
PubMed1981

Ketoprofen pharmacokinetics and bioavailability based on an improved sensitive and specific assay.

A commercial capsule containing 50 mg of ketoprofen (Orudis), a simple capsule containing 50 mg of ketoprofen alone and 50 mg of ketoprofen in an aqueous solution were given as separate doses in a randomized sequence to 12 normal adult males. The areas under the resulting plasma concentration-time curves (AUC) were remarkably consistent for each volunteer. The bioavailability from the commercial capsule relative to that from the solution was 99.7% +/- 10.5% and that from the simple capsule was 102% +/- 10%. After 6 of the volunteers had taken the commercial capsule 6 hourly for thirteen doses, their AUC extrapolated to infinity was significantly higher (by 22%) than that after the single dose indicating, contrary to previous reports, accumulation upon multiple dosing. The interdose AUC after the thirteenth dose was, however, statistically indistinguishable from the AUC-to-infinity after the single dose as might be expected from linear kinetics. The ketoprofen solution generated peak plasma concentrations in only one-third the time (21 +/- 7 min) required for the capsules (commercial, 72 +/- 45; simple, 61 +/- 39 min). Despite plasma concentrations being tracked over a 200-fold range, log linearity was not established within 12 h in any of the 42 profiles obtained. A two-compartment open model was fitted to the solution data giving excellent prediction of the time-to-peak and clearance (Cl/F = 5.2 +/- 1.1l/h) as determined by eye and by log-trapezoidal rule, respectively.

Biological Availability↗
PubMed1981

The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration--effect relationships.

1 A combined pharmacokinetic and pharmacodynamic model has been used to analyze the relationship between electrocardiographic (ECG) and systolic time intervals (STI) and changes in plasma concentration of quinidine after oral and i.v. doses in ten normal subjects. 2 The major effects of quinidine were on cardiac repolarization. Contrary to previous descriptions, we found no important change in the U wave, but the T wave was split into two peaks. The amplitude of these two peaks (T and T') was reduced, and the QT' peak and QT intervals were prolonged. The QT peak interval and systolic intervals did not change appreciably. There were small increases in the PQ and QRS intervals. 3 The effect of quinidine on the QT interval could be explained by a linear pharmacodynamic model. The equilibration between plasma and effect site had a half-time of 8 min. The slope of the pharmacodynamic model was 20.3 ms . mg 1(-1) after i.v. dosing and 33.5 ms . mg 1(-1) after oral dosing. 4 The difference in effect model slopes suggests pharmacologically active metabolites of quinidine are formed during absorption from the gut. 5 The total effect of a single oral dose of quinidine appears to be the same as the same dose given intravenously, even though only 70% of the oral dose reaches the systemic circulation as quinidine.

Biological Availability↗
PubMed1980

Convenient and sensitive high-performance liquid chromatography assay for ketoprofen, naproxen and other allied drugs in plasma or urine.

A new high-performance liquid chromatography technique enables convenient and rapid assay of ketoprofen and naproxen in biological samples at a sensitivity (10 and 2 ng/ml, respectively in plasma; 20 and 50 ng/ml in urine) far greater than previously available. Superior sensitivity is attributable to the buffered neutral eluent employed, which yields improved separation from material of biological origin. There is no interference from the major ketoprofen and naproxen metabolites tested and excellent reproducibility and accuracy can be maintained. Moreover, the same system can be used to assay probenecid and also shows promise of applicability to ibuprofen, fenoprofen and other members of the aryl-alkanoic acid class of non-steroidal anti-inflammatory agents.

Chromatography, High Pressure Liquid↗
PubMed1980

Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria.

The bioavailability of theophylline from alcoholic and aqueous oral solutions was compared to that from an intravenous dose in 12 normal adults. The alcoholic elixir surprisingly gave rise to a significantly greater (114 +/- 14%, mean +/- SD) amount absorbed than did the intravenous dose. The aqueous solution (99 +/- 8%) and intravenous dose were statisticlly indistinguishable in this respect, and, furthermore, the extent of absorption from a 300-mg dose of the aqueous solution was 99 +/- 10% of that from a 500-mg dose, and not statistically different. The aqueous solution was thus employed in three subsequent studies as a standard with which to compare 13 different types of theophylline tablets, all marketed in the United States. Of the 13 tablets, eight showed bioavailability statistically distinguishable from that of the standard. Nevertheless, for only two tablets could it be claimed with 95% confidence level that the bioavailability was less than 95%. For none can it be stated at this confidence level that the bioavailability is less than 90%. Bioavailability studies should include criteria of clinical significance in addition to criteria of statistical significance. Contrary to the usual rationale behind choice of a bioavailability standard, nine of the 12 uncoated tablets appeared to allow more rapid absorption of theophylline than did the standard oral solution, an aqueous syrup. Increasing the dose of syrup decreased the rate of theophylline absorption. Orally administered drug solutions may have properties more absorption rate limiting than the disintegration of many brands of tablet.

Absorption↗