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S Riegelman

Publications and source records attributed to S Riegelman.

At least 37 records · Page 2Linked to original sources
PubMed1982

Lack of gastrointestinal metabolism of propranolol in dogs after portacaval transposition.

We studied whether or not propranolol underwent presystemic metabolism in the gastrointestinal wall in five dogs. The dogs were studied before and four weeks after creation of a portacaval transposition. Before surgery, systemic bioavailability of the oral dose was 8 +/- 8% (mean +/- S.D.), whereas after transposition the bioavailability was 102 +/- 9%. The systemic plasma clearance increased from 766 +/- 192 to 976 +/- 280 ml/min. The terminal half life and apparent volume of distribution after transposition were not significantly different from those obtained preoperatively. Our results indicate that there is complete absorption but no metabolism of propranolol by the gastrointestinal wall.

Administration, Oral↗
PubMed1982

Improved liquid-chromatographic assay of quinidine and its metabolites in biological fluids.

We describe a simple, rapid, and specific assay for quinidine and its known metabolites in plasma, urine, and bile. Plasma proteins are precipitated by adding acetonitrile, which also contains the internal standard. The supernatant fluid is evaporated and the reconstituted residue is separated on a reversed-phase column, with fluorescence detection. The standard curve is linear and results are reproducible over the clinical concentration ranges: quinidine 0.4 to 8.0 mg/L and the three metabolites (quinidine 10,11-diol, 3-hydroxyquinidine, and quinidine-N-oxide) 0.05 to 1.5 mg/L. As little as 10 micrograms of the N-oxide metabolite per liter and 1 microgram of the other analytes per liter can be quantitated in 0.5 mL of plasma, urine, or bile. With the use of an automated chromatographic system, many samples can be analyzed in a continuous run.

Animals↗
PubMed1981

Measurement of excretion characteristics of theophylline and its major metabolites.

Analysis of urinary excretion after administration of 320 mg of theophylline to six normal volunteers appears to indicate the occurrence of capacity limited formation of most of the theophylline metabolites and non-linear renal excretion of theophylline. The renal clearance is elevated at high concentrations where the metabolic clearance is reduced. Even though the individual process of elimination is non-linear, the compensating relationship appears to yield a constant total elimination clearance. The implication of these results in chronic therapy and dose adjustment is discussed.

Humans↗
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

Effect of erythromycin on theophylline kinetics.

The effect of erythromycin base on theophylline kinetics was studied in eight informed, nonsmoking, adult males who received a 15-min infusion of theophylline (aminophylline) 5 mg/kg, prior to (control) and after (experimental) a 7-day course of 1 gm daily erythromycin base (E-Mycin). Each subject acted as his own control. Multiple serum samples were collected for 24 hr after each dose and were analyzed for theophylline by high-pressure liquid chromatography. The mean +/- SD pharmacokinetic parameters for each phase of study were as follows: apparent volume of distribution (L/kg) 0.45 +/- 0.05 (control), 0.41 +/- 0.05 (experimental); clearance (ml . min/kg) 0.83 +/- 0.17 (control), 0.60 +/- 0.11 (experimental); elimination half-life (hr) 6.65 +/- 1.88 (control), 8.10 +/- 1.58 (experimental). Erythromycin significantly affected the elimination half-life and clearance of theophylline (p less than 0.05). The apparent volume of distribution was unaffected (p greater than 0.05). Therefore patients being administered theophylline appear to be at added risk for the development of toxicity when erythromycin is added to the therapeutic regimen.

Adult↗
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↗
PubMed1981

Metabolism of theophylline to caffeine in adults.

Caffeine and its major metabolite, paraxanthine, were observed in plasma following oral administration of theophylline in a multiple dose study. At steady state, plasma caffeine concentrations varied from 0.21 to 0.75 mg/L at plasma theophylline concentrations of 8.1 to 21.5 mg/L in four healthy subjects. About 6% of the theophylline dose was converted to caffeine, which is further metabolized to a series of degradation products, which can be measured after caffeine administration, accounted for the incomplete urinary recovery usually observed after theophylline administration.

Adult↗
PubMed1980

Simultaneous determinations by theophylline and its major metabolites in urine by reversed-phase ion-pair high-performance liquid chromatography.

A new, highly slective high-performance liquid-chromatographic (HPLC) assay for theophylline and its major metabolites in urine is described. The method utilizes an ion-pair extraction followed by separation and quantitation by reversed-phase ion-pair gradient-elution HPLC. Comparison with several other methods showed that interferences were present in too many blank urine samples to allow for the accurate quantitation of the metabolites of theophylline by direct injection--isocratic HPLC assays. Sample processing involving ion-pair complexing and extraction together with gradient-elution systems is recommended for accurate pharmacokinetic studies.

Chromatography, High Pressure Liquid↗
PubMed1980

Determination of propranolol and its major metabolites in plasma and urine by high-performance liquid chromatography without solvent extraction.

Fast, reliable, specific and sensitive methods are reported to accurately quantitate unchanged, propranolol in plasma, and its major metabolites in plasma and urine after enzymatic hydrolysis without the need for solvent extraction. These methods enable the analyst to process a large number of propranolol samples in one working day and should prove valuable to clinical laboratories demanding both speed and specificity in an assay.

Chromatography, High Pressure Liquid↗
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

Negligible excretion of unchanged ketoprofen, naproxen, and probenecid in urine.

On the average, 0.6% of a dose of ketoprofen or naproxen or 1.2% of a dose of probenecid was found in the urine of normal male volunteers assayed immediately after its collection. Between approximately 60 and 85% of the dose of these drugs can be excreted in the urine as conjugates, which rapidly hydrolyze at body temperature, at room temperature, and even during frozen storage, thereby regenerating the parent drug. Since urine collections involved sample retention in the bladder at 37 degrees for collection intervals as long as 2--3 hr, the given percentages excreted unchanged probably are overestimates. It is possible that no unchanged ketoprofen, naproxen, or probenecid is excreted in urine. This study contrasts with previous reports of up to 50% of a dose of ketoprofen and 15--17% of doses of naproxen and probenecid being excreted in urine as the parent compound. Those reports probably reflect primarily the duration of frozen sample storage between collection and assay along with the urine collection schedules employed the speed of the clinical procedures, and the analytical procedures used. Attention should be given to potential conjugate hydrolysis whenever the pharmacokinetics of carboxylic acids are studied.

Humans↗
PubMed1980

The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time.

Moments analysis has been applied to the calculation of mean (in vivo) dissolution time (MDT) and mean absorption time (MAT) from plasma level of drug versus time data. Methods for accurately estimating the MDT under varying conditions, limitations of the methods, and interpretation of the data are presented. The importance of accurate estimates of the terminal rate constant (lambda 2) and the drug concentration at the time of withdrawing the final plasma sample (Cz) is emphasized in connection with extrapolation to t = affinity. The appropriate use of a logarithmic trapezoidal equation for calculating the area under the moments curve (AUMC) is shown to increase the accuracy of estimating MDT.

Absorption↗
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↗
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↗