Biomedical subjects

S Symchowicz

Publications and source records attributed to S Symchowicz.

At least 19 recordsLinked to original sources

PubMed1989

Single and multiple dose pharmacokinetic evaluation of flutamide in normal geriatric volunteers.

Single dose and steady-state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9. After oral administration, F was rapidly absorbed and metabolized. It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects. Steady-state plasma concentrations were reached on or before Day 6. The mean steady state Cmax (Day 9), 112.7 ng/ml, occurred at 1.3 hr. Pharmacokinetic analysis of mean data at steady-state gave a distribution and elimination half-life of 0.8 hr and 7.8 hours, respectively. The plasma levels for HF were much higher and less variable than F. The mean Cmax for HF averaged 894 ng/ml at 2.7 hours after a single dose and 1719 ng/ml (Day 9) at 1.9 hr after multiple doses. The distribution and elimination half-lives of HF at steady-state were 1.9 and 9.6 hours, respectively. The steady-state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose. From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day.

Administration, Oral↗

PubMed1989

Influence of food on the absorption of albuterol Repetabs.

A study was conducted in 12 healthy, nonsmoking male volunteers to examine the effect of food intake on the absorption profile of albuterol repeat-action tablets. This randomized crossover study consisted of two phases separated by a 1-week washout period. All subjects fasted 10 hours preceding drug administration. Each subject received two 4 mg albuterol repeat-action tablets with and without a high fat content breakfast. Plasma albuterol concentrations were determined by a gas chromatographic/mass spectrophotometric assay. Relative bioavailability was assessed by comparing areas under the plasma-albuterol concentration time curves as well as peak concentrations and time to peak concentration. No significant differences were noted between the two treatment phases in the area under the curve or peak plasma concentrations. The areas under the curve were 100 and 105 hr.ng/ml when the drug was administered with and without food, respectively. The corresponding peak plasma concentration values were 9.4 and 10.4 ng/ml, respectively. The only significant difference observed was in the maximum time to reach peak plasma concentrations, which was delayed by about 1 hour when the drug was administered with food. Therefore, food has minimal effect on the absorption of albuterol from repeat-action tablets.

Adult↗

PubMed1988

Excretion of loratadine in human breast milk.

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40-mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration-time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration-time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and 4.2 micrograms of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8-hour collection interval. Through 48 hours, the mean milk-plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 micrograms of descarboethoxyloratadine (7.5 micrograms loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4-kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Pharmacokinetics and bioavailability of dilevalol in normotensive volunteers.

The bioavailability and pharmacokinetics of dilevalol following oral and intravenous administration were investigated in 12 healthy male volunteers. Dilevalol HCl was administered as a 200-mg oral tablet and a 50-mg intravenous infusion using a randomized cross-over design. Blood and urine samples were collected over 60 hours and analyzed for unchanged and total (unchanged plus Glusulase-released) dilevalol using a high performance liquid chromatography (HPLC) assay. After intravenous administration, total body clearance and volume of distribution of unchanged dilevalol were determined to be 23.2 mL/min/kg and 24.6 L/kg, respectively. After oral administration, a mean maximum concentration of 62 ng/mL was reached at an average peak time of 1.4 hours. Drug was eliminated with a half-life of 8.3 hours after oral administration and 12 hours after intravenous administration. Based on plasma levels and urinary excretion of total dilevalol, the drug was completely absorbed; however, due to first-pass metabolism, the absolute bioavailability of unchanged drug was 11 to 14%.

Administration, Oral↗

PubMed1988

Secretion of dilevalol in breast milk.

The pharmacokinetics of unchanged and total (unchanged plus Glusulase [Biotechnology Systems, Boston, MA]) released dilevalol and secretion into human breast milk was studied in six healthy breast-feeding female volunteers administered a single 400-mg dilevalol hydrochloride capsule. In plasma, the mean Cmax for unchanged dilevalol, 485 ng/mL was reached at 0.8 hour (tmax) and the AUC(48 hours) was 1435 hr X ng/mL. Pharmacokinetic analysis of unchanged dilevalol in plasma showed that dilevalol was distributed and eliminated with half-lives of 0.9 and 8.2 hours, respectively. Breast milk concentrations of unchanged dilevalol as a function of time, paralleled those of plasma but were consistently lower. The milk Cmax, 149 ng/mL, occurred during the 0 to 2 hour collection interval; the AUC(42 hours) for unchanged dilevalol in milk was 663 hr X ng/mL. The mean milk to plasma concentration ratio was 0.46. The unchanged dilevalol plasma concentrations were 12 to 18% those of total drug suggesting that the drug is extensively conjugated. By contrast, the concentrations of unchanged dilevalol in breast milk, based on Cmax and AUC data were 63 to 94% those of total drug, indicating that very little conjugated drug is secreted into breast milk. Through 48 hours, a mean of only 27 micrograms dilevalol or 0.007% of the administered dose was secreted into breast milk, which is much less than that reported for other beta blockers.

Administration, Oral↗

PubMed1987

Loratadine: multiple-dose pharmacokinetics.

The steady-state pharmacokinetics of loratadine (L), a new long-acting antihistamine devoid of CNS activity, was investigated in 12 healthy male volunteers. Each volunteer received 40-mg L capsules q24h for ten days. Blood samples were collected at various times on day 1, 5, 7, and 10 and assayed for L by radioimmunoassay (RIA) and for descarboethoxyloratadine (DCL), a known active metabolite, by high-performance liquid chromatography (HPLC). The plasma L and DCL concentration-time data in the disposition phases were fitted to a biexponential equation for pharmacokinetic analysis. Steady-state plasma L Cmax concentrations were reached at 1.5 hour (Tmax) after each dose. DCL steady-state Cmax values ranged 26 to 29 ng/mL at a Tmax ranging from 1.8 to 3 hours. The AUC at steady state, AUC tau, was 80 to 96 and 349 to 421 h X ng/mL for L and DCL, respectively. The accumulation indexes (Ra) based on AUC tau ratios, did not change for either compound after day 5. Ra values for L and DCL after the fifth dose were 1.4 and 1.9, respectively, indicating that there is little accumulation of either L or DCL after a multiple (once-a-day) dosage regimen. The t1/2 beta at steady state were 14.4 and 18.7 hours for L and DCL, respectively, which were similar to those reported following a single-dose L administration. Observed plasma drug concentrations were in good agreement with predicted values derived for pharmacokinetic parameters.

Adult↗

PubMed1987

Pharmacokinetics and dose proportionality of loratadine.

The dose proportionality and pharmacokinetics of loratadine, a new nonsedating antihistamine, were studied in 12 normal volunteers. In a three-way cross-over, each volunteer received a single 10-, 20-, or 40-mg loratadine capsule. Blood was collected up to 96 hours after dosing. Plasma loratadine concentrations were determined by radioimmunoassay (RIA), and those of a minor, but active metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Concentrations in the disposition phase were fitted to a biexponential equation for pharmacokinetic analysis. For dose proportionality, AUC- and Cmax-dose relationships were evaluated by linear regression. Also, pharmacokinetic parameters and dose-adjusted AUCs were compared by analysis of variance. Loratadine was rapidly absorbed, reaching Cmax values (4.7, 10.8, and 26.1 ng/mL) at 1.5, 1.0 and 1.2 hours for the 10-, 20-, and 40-mg doses, respectively. The loratadine t1/2 beta ranged from 7.8 to 11.0 hours. Descarboethoxyloratadine reached Cmax values (4.0, 9.9, and 16.0 ng/mL) at 3.7, 1.5, and 2.0 hours for the 10-, 20-, and 40-mg doses, respectively. Its t1/2 beta ranged from 17 to 24 hours. For both compounds, AUC- and Cmax-dose relationships were linear and there were no differences in the t1/2 beta, CL/F, or dose-adjusted AUC values among the treatments. Loratadine and descarboethoxyloratadine plasma concentrations and pharmacokinetics were not dose dependent.

Administration, Oral↗

PubMed1987

Pharmacokinetics and metabolism of an intravenously administered penem (Sch 34343) in humans.

The pharmacokinetics of Sch 34343, a new broad-spectrum penem antibiotic, was studied in subjects receiving 1 g of 14C-labeled drug by intravenous administration. At the end of a 30-min intravenous infusion, the mean maximum concentration of drug in serum was 39 micrograms/ml for unchanged Sch 34343 and 49 mu eq/ml for total radioactivity. The mean serum half-lives of Sch 34343 were 0.16 h for the distribution phase and 0.80 h for the elimination phase. The total body clearance of Sch 34343 was 7.52 ml/min per kg, and the mean apparent volume of distribution was 525 ml/kg. Over a 4-day period, mean urinary excretion of radioactivity accounted for 87.9% of the dose, and mean urinary excretion of unchanged Sch 34343 accounted for 23.6% of the dose. The total radioactivity in feces on days 0 to 6 accounted for only 0.8% of the dose. In serum from 0.5 and 1 h, unchanged Sch 34343 represented the major radioactive peak, with negligible amounts of several metabolites. In urine, there were at least six metabolites in addition to Sch 34343. The amount of unchanged Sch 34343 accounted for 33% of radioactivity in samples of urine from 0 to 2 h, 22% in urine from 2 to 4 h, 15% in urine from 4 to 8 h, and 0% in urine from 8 to 12 h.

Adult↗

PubMed1987

Evaluation of (+)-cyclaradine-5'-esters as prodrugs for (+)-cyclaradine in animals.

Both (+)-cyclaradine-5'-methoxyacetate (CM) and (+)-cyclaradine-5'-ethoxypropionate (CE) were converted to (+)-cyclaradine (C) in squirrel monkey and human sera at 37 degrees C. CE was more stable than CM. After oral administration (20 mg base equivalent per kg) of either CM or CE, no unchanged esters were observed in serum of squirrel monkeys, rabbits, or rats. Instead, C was detected, indicating conversions of CM and CE to C in vivo. In squirrel monkeys, the areas under the curve (AUCs) of C obtained from oral dosing with CM were 61% higher than those obtained from dosing with C, indicating that CM may be a good prodrug for C. In squirrel monkeys, rabbits, and rats, CE resulted in a 20 to 90% higher AUC of C than did CM, indicating that CE was better absorbed than CM.

Administration, Oral↗

PubMed1986

Relationships of brain and plasma levels of quazepam, flurazepam, and their metabolites with pharmacological activity in mice.

The relationships between the pharmacological activities of quazepam and flurazepam and the concentrations of each drug and its major active metabolites in brain and plasma following single oral doses of either drug to mice were investigated. At various time points after either quazepam or flurazepam administration, pharmacological activity was measured by the inhibition of electroconvulsive shock (ECS)-induced seizures. After quazepam, the plasma and brain samples obtained at the same time points were assayed for concentrations of quazepam, 2-oxoquazepam and N-desalkyl-2-oxoquazepam by specific GLC methods. After flurazepam, the plasma and brain samples were assayed for flurazepam, hydroxyethyl-flurazepam, and N-desalkyl-2-oxoquazepam, also by specific GLC methods. The results showed that both quazepam and flurazepam were rapidly metabolized and that parent drugs and metabolites were rapidly distributed to the brain. The brain levels of all the benzodiazepines analyzed in this study paralleled plasma levels. After quazepam, pharmacological activity most closely paralleled the combined brain concentrations of quazepam and 2-oxoquazepam rather than N-desalkyl-2-oxoquazepam levels. In contrast, following the flurazepam dose, activity most closely paralleled N-desalkyl-flurazepam concentrations. From these data, it can be concluded quazepam is distinctly different from flurazepam, and that, in the presence of quazepam and 2-oxoquazepam, N-desalkyl-2-oxoquazepam does not contribute extensively to the observed pharmacological activity.

Animals↗

PubMed1986

Rising multiple-dose pharmacokinetics of labetalol in hypertensive patients.

Labetalol, a drug possessing both alpha- and beta-adrenergic blocking activities, is used in the treatment of hypertension. The current study was undertaken to elucidate the steady-state pharmacokinetics of labetalol following a rising oral multiple-dosage regimen. Twelve patients received oral labetalol every 12 hours for 18 days. An initial dose of 100 mg was increased at three-day intervals to 200, 300, 400, and 600 mg q12h. Selected blood samples were taken at various times following drug administration at each dose level and analyzed for labetalol levels by a specific high-performance liquid chromography assay. The pharmacokinetics of labetalol are best described by a two-compartment open model with first-order absorption. The half-lives of the absorption, distribution, and elimination phases are 0.6, 1.3, and 8.3 hours, respectively. The steady-state plasma drug concentrations are predictable from the pharmacokinetic data and are in good agreement with the observed values. Steady-state levels are reached by the third day at each dose level studied and increase proportionally with dose.

Adult↗

PubMed1986

Pharmacokinetics and metabolism of [14C]rosaramicin in dogs.

The pharmacokinetics and metabolism of [14C]rosaramicin were studied in dogs after intravenous (i.v.; 10 mg/kg [bodyweight]) and oral (25 mg/kg) administration. After i.v. administration, rosaramicin levels in plasma declined rapidly, with half-lives of 0.22 h for the distribution phase and 0.97 h for the elimination phase. The apparent volume of distribution was 3.43 liters/kg, and the total body clearance was 106 mg/min . kg, indicating extensive distribution in tissue or metabolism or both. The absorption of oral solution was 58%, and the absolute bioavailability of rosaramicin was 35%. The plasma area under the curve of unchanged rosaramicin was only 5% that of total radioactivity after oral administration and 8% after i.v. administration, indicating extensive metabolism of the drug. The total radioactivity excreted in urine accounted for only 24% of the i.v. dose and 17% of the oral dose. Fecal radioactivity accounted for 71% of the i.v. dose and 68% of the oral dose. Several metabolites were observed in the plasma and urine. The amount of unchanged rosaramicin in urine (1 to 2% of the dose) was quite small after drug administration by either route.

Administration, Oral↗

PubMed1985

The excretion of rosaramicin in breast milk.

The excretion of rosaramicin, a macrolide antibiotic, was studied in the breast milk of ten lactating women. Breast milk and serum samples were collected for 48 hours after a single 250-mg oral dose of rosaramicin. Mean serum half-life, apparent volume of distribution, and oral clearance were 4.4 hours, 3.41 L/kg, and 6.34 mL/min/kg, respectively. Mean milk/serum ratio was 0.12 and the total amount of drug recovered over the first ten hours was 6.25 micrograms, approximately 0.0025% of the dose. A positive correlation between breast milk volume and breast milk clearance was found, suggesting that the amount of drug received by a nursing infant will depend on the volume of milk produced by the mother. Drug-induced toxicity from the parent drug is unlikely to occur in nursing infants since the amount of rosaramicin that a nursing infant could ingest is small.

Adult↗

PubMed1985

Steady-state bioavailability of dexbrompheniramine and pseudoephedrine from a repeat-action combination tablet.

The steady-state bioavailabilities of dexbrompheniramine and pseudoephedrine were evaluated following multiple-dose administrations of a repeat-action combination tablet containing 6 mg of dexbrompheniramine maleate with 120 mg of pseudoephedrine sulfate every 12 h for 7 d compared with reference standards. The reference standards used in this study were concomitant administration of conventional 2-mg dexbrompheniramine maleate tablets every 4 h and 120-mg pseudoephedrine sulfate repeat-action tablets every 12 h, each for 7 d. Twelve healthy adult male volunteers completed this randomized two-way crossover study. Blood samples for subsequent assay were obtained at frequent time intervals throughout each 7-d dosing phase. Sensitive and specific gas-liquid chromatographic methods were used for the determination of dexbrompheniramine and pseudoephedrine in plasma. Based on the plasma levels, the times to reach steady state were determined. In addition, the major bioavailability parameters (Cmin, Cmax, tmax, and AUC) for days 6 and 7 of dosing were determined and statistically evaluated. The results of this study demonstrate that, at steady state, the repeat-action combination tablet and concomitant administration of the reference standards are bioequivalent.

Biological Availability↗

PubMed1985

Interspecies pharmacokinetic scaling of Sch 34343.

Pharmacokinetic parameters of Sch 34343 have been determined for mice, rats, rabbits, monkeys, dogs and humans and correlated among species as an exponential function of body weight. The pertinent pharmacokinetic parameters tested are apparent and steady-state volumes of distribution, total body clearance, elimination phase half-life, and mean residence time. This study showed that the extrapolation of animal data to humans on a new investigational drug, Sch 34343, can be potentially useful.

Animals↗

PubMed1984

Excretion of quazepam into human breast milk.

Previous metabolic studies have established that two major metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15-mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2-oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam through 48 hours was only 0.11 per cent.

Adult↗

PubMed1984

Multiple-dose halazepam kinetics.

Halazepam is a benzodiazepine used in the management of anxiety disorders or short-term relief of anxiety. Our study was undertaken to evaluate its steady-state kinetics and those of its major active plasma metabolite N- desalkylhalazepam . Eleven healthy men aged 19 to 35 yr were given oral, 40-mg halazepam tablets every 8 hr for 14 days. Plasma samples were analyzed by gas chromatography to determine levels of halazepam and N- desalkylhalazepam . Halazepam kinetics can best be described by a two-compartment open model with first-order absorption kinetics. The elimination phase t1/2s of halazepam and N- desalkylhalazepam were 34.7 and 57.9 hr. Steady-state levels were predictable from kinetic data and were reached by the third day for halazepam and by the eleventh day for N- desalkylhalazepam .

Adult↗

PubMed1984

Effect of sleep on quazepam kinetics.

The effect of sleep on quazepam kinetics was studied in 12 normal adult men. In a randomized two-way crossover design, each subject received one 15-mg quazepam tablet either at night just before sleep or in the morning after a night's sleep. Blood samples were drawn before and at specified times (to 120 hr) after dosing. To assure that blood collection did not interfere with sleep, blood was drawn by an indwelling catheter from a large arm vein. Plasma concentrations of quazepam and its two major plasma metabolites (which are also active) 2-oxoquazepam and N-desalkyl-2-oxoquazepam (N-desalkylflurazepam) were determined by specific GLC methods. Kinetic analysis was by a two-compartment open model with first-order absorption/formation kinetics. Quazepam was rapidly absorbed with both administration times; absorption t 1/2 was 0.7 to 0.9 hr. Absorption lag time was slightly longer after the nighttime dose (1.0 and 0.6 hr). Maximum concentration and AUC of quazepam and 2-oxoquazepam and AUC of N-desalkyl-2-oxoquazepam were somewhat higher after nighttime dosing, most likely a result of decreased apparent volume of distribution of the central compartment after the nighttime dose (5.0 l/kg for nighttime dosing and 8.6 l/kg for morning dosing). The elimination t 1/2s of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam after the morning dose were 25, 28, and 79 hr, which did not differ from those values after the nighttime dose. In general, time of dosing had no appreciable effect on quazepam kinetics or those of its major active plasma metabolites. The small differences between the two dose times are not expected to have clinical significance.

Absorption↗