Computation of model-independent pharmacokinetic parameters during multiple dosing.
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Humans↗
Biomedical subjects
M Chung
Publications and source records attributed to M Chung.
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↗
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↗
Quazepam kinetics in the elderly.
The kinetics of quazepam, a benzodiazepine hypnotic, was studied in 10 geriatric subjects. Each received one 15-mg tablet of quazepam. Blood samples were collected before and at specified times (up to 672 hr) after dosing. Plasma concentrations of quazepam and its two major active plasma metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), were determined by specific GLC methods. Kinetics were best described by a two-compartment open model with first-order absorption/formation kinetics and standard equations. Quazepam was rapidly absorbed, with a t1/2 of 0.8 hr. The mean maximum plasma level (Cmax) was 29.3 ng/ml. The disposition t1/2s in the distribution (t1/2 alpha) and elimination (t1/2 beta) phases were 3.5 and 53.3 hr. 2-Oxoquazepam was rapidly formed with quazepam, with an apparent formation t1/2 of 0.8 hr. Mean Cmax was 14.5 ng/ml. The t1/2 alpha and t1/2 beta of 2-oxoquazepam were 4.2 and 43.1 hr, of the order of those of quazepam. The t1/2 beta of N-desalkyl-2-oxoquazepam, formed from 2-oxoquazepam, was 189.7 hr, much longer than that of its precursor. Comparison of these data with reported kinetic data in young subjects shows that t 1/2 betas of quazepam and 2-oxoquazepam increased only slightly or not at all with age, but that the t 1/2 beta of N-desalkyl-2-oxoquazepam in the elderly was more than twice that in young subjects.
Absorption↗
Multiple-dose quazepam kinetics.
Quazepam, a benzodiazepine hypnotic, was studied in normal subjects to evaluate steady-state kinetics of quazepam and of its major active plasma metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, after 15 mg once daily by mouth for 14 days. The kinetics of quazepam and 2-oxoquazepam can be best described by a two-compartment open model with first-order absorption/formation kinetics. Quazepam was rapidly absorbed and its two major plasma metabolites appeared very quickly in systemic circulation. The elimination t 1/2s of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 41, 43, and 75 hr. Steady-state levels were predictable from the kinetic data and were reached by the seventh dose for quazepam and 2-oxoquazepam and by the thirteenth dose for N-desalkyl-2-oxoquazepam. These kinetic profiles may explain the clinical hypnotic effect of quazepam--rapid induction of sleep and long duration of clinical action without appreciable rebound insomnia.
Absorption↗
Pharmacokinetics and metabolism of rosaramicin in humans.
The pharmacokinetics of rosaramicin was studied in subjects receiving 500 mg of the drug (i) by 1-h intravenous infusion, (ii) in solution orally, or (iii) as tablets orally. After intravenous administration, the rosaramicin levels in serum declined rapidly with t1/2S of 0.27 h for the distribution phase and 3.28 h for the elimination phase. The apparent volume of distribution was 3.78 liter/kg, and the total body clearance was 13.41 ml/min per kg, indicating extensive tissue distribution or metabolism or both. Similar pharmacokinetic data were obtained after oral administration of the drug in solution or tablets and after intravenous dosing. The absolute bioavailability of the drug administered orally, in either tablets or solution, was 32 to 39%. The metabolism and excretion of [14C]rosaramicin administered orally were also evaluated in volunteers. The serum area under the curve (infinity) of unchanged rosaramicin was 19% of that of total radioactivity, indicating extensive metabolism of the drug. About 7.0% of the radioactivity was recovered in the urine, and 86.7% was recovered in the feces. Only a small amount of unchanged rosaramicin was present in the urine (7 to 9% of urinary radioactivity), but none was present in the feces. The major metabolite, 20-bis-ureidorosaramicin, represented 17 to 38% of the radioactivity in the urine and 26 to 29% of the radioactivity in the feces.
Administration, Oral↗
Effect of intestinal anaphylaxis on gut function in the rat.
We examined the effect of intraluminal antigen on intestinal function in an animal model of anaphylaxis using Hooded-Lister rats sensitized to ovalbumin. Older rats were more difficult to sensitize than younger ones; younger rats more consistently developed antiovalbumin titers of greater than or equal to 1:64 as measured by passive cutaneous anaphylaxis. That these immunoglobulins were of the immunoglobulin E class was suggested by the fact that heating of the sera to 56 degrees C for 3 h eliminated the response. Net fluxes of water and electrolytes were measured in sensitized rats with serum titers greater than or equal to 1:64 and compared with nonsensitized sham-treated controls during two periods: when the perfusate was antigen-free and after the addition of antigen. Intraluminal antigen challenge had no effect in controls but caused a rapid and dramatic reduction in water, Na+, Cl-, and K+ absorption in experimental animals (greater than or equal to 1:64). There was no evidence of recovery after antigen withdrawal, and the response was antigen-specific. Mucosal homogenates prepared after antigen challenge in sensitized animals contained significantly less histamine than homogenates prepared from controls, and granulated mucosal mast cell numbers were reduced. Light microscopy did not reveal any alteration of villus height or crypt depth, but mucosal edema was apparent in sections from sensitized animals. The findings suggest that anaphylactic reactions to food proteins in the intestine lead to abnormalities of water and electrolyte absorption and that histamine, or other mast cell mediators, or both, may be responsible.
Anaphylaxis↗
Study of single and multiple dose pharmacokinetic/pharmacodynamic modeling of the antihypertensive effects of labetalol.
This was an open-label, two-phase crossover study of labetalol in 11 patients with mild to moderate hypertension. A two- to four-week outpatient placebo phase was followed by a three-day inpatient placebo period. Patients were then randomly assigned to receive either labetalol, 200 mg, as a single dose and three times a day for three days and, on the final day, another single dose or a similar sequence with 300 mg as the single dose and multiple twice a day treatment. A two-week placebo outpatient period was followed by the second phase of the study in which the treatment regimen was reversed for the two groups. Blood samples for the determination of free and conjugated labetalol plasma levels were collected, and blood pressures and heart rate were recorded sequentially for 24 hours after the first and last dose of labetalol, and during the multiple dose treatment period before and two hours after each dose as well as four times daily with the patient supine and upright. Of the 11 patients analyzed, five were men and six were women, ranging in age from 33 to 62 years. Labetalol (200 mg and 300 mg) was rapidly absorbed with peak concentrations achieved in approximately one hour. The pharmacokinetic data best fit a two-compartment pharmacokinetic model with first order absorption. At steady state, the absorption, distribution, and elimination kinetics were similar for both dosage regimens with elimination half life of 7.65 and 7.92 hours for the 200 mg three times a day and 300 mg twice a day regimens, respectively. During the multiple dosing period average steady-state plasma drug concentrations were 0.149 mg/ml and 0.145 mg/ml for the 300 mg twice a day and 200 mg three times a day regimens, respectively. Approximately 12 percent of total plasma labetalol was free drug. The balance was conjugated. The first dose of 200 mg or 300 mg of labetalol significantly (p less than 0.01) lowered standing and supine mean blood pressure over a period of eight to 12 hours, respectively, with peak effects occurring at two (standing) and four (supine) hours. A significant reduction (p less than 0.01) in supine mean blood pressure was present 24 hours after the initial dose of 300 mg. At steady state the antihypertensive effects of the 200 mg three times a day and the 300 mg twice a day dosage regimens were similar.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Postnatal development of glucose transport in the proximal small intestine of the rabbit.
Developmental change in intestinal solute transport was examined by studying glucose transport in rabbit jejunal tissue at age intervals after birth. Net D-glucose absorption was greater in jejunum from suckling rabbits (10-14 days old) compared to older animals when studied in Ussing-type short-circuited chambers, and jejunal tissue slices from these younger animals accumulated more intracellular D-glucose. Net fluxes of 3-0-methyl-D-glucose were also greater in jejunum from the younger age group, excluding this effect being due to substrate metabolism. Increased permeability of jejunal epithelium in immature animals was evidenced by larger unidirectional fluxes and higher conductance. The findings suggest that the developing jejunum, although more permeable, has an increased capacity for active sugar transport, a pattern differing from that seen with most other intestinal absorptive functions.
3-O-Methylglucose↗
Evaluation of technique for autotransplantation of the spleen in dogs.
Preservation of the human spleen is important in the prevention of overwhelming sepsis, particularly in infants and immunosuppressed patients. When that preservation is not possible, due to disease or severe trauma, it has been suggested that autotransplantation of splenic tissue might provide adequate immunological protection. This study looked at the feasibility of autotransplantation via subcutaneous implantation in the dog. This method is important, since controlled intraabdominal splenosis is very difficult to achieve. The adverse effect of splenectomy, as well as the ineffectiveness of autotransplantation was demonstrated in providing demonstrable in vitro evidence of decreased sheep red blood cell immunization, even though the subcutaneous implantation itself was successful. From this study, the authors suspected, but could not prove, that the ineffectiveness of the splenic autotransplants was related to their lack of critical mass for good bacterial clearance from the blood stream and the fact that they did not lie within the main vascular channels, probably a criterion for proper clearance. The role of splenic preservation by autotransplantation needs to be evaluated in the immature host.
Agglutination Tests↗
Evaluation of the in-vitro activity of Sch 29482.
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Administration, Oral↗
Pharmacokinetics of Sch 29482 in rats.
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Administration, Oral↗
Oral absorption and tolerance in man, of a new penem antibiotic, Sch 29428.
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Adult↗
Comparative pharmacokinetics of aminoglycoside antibiotics in guinea pigs.
The pharmacokinetics of netilmicin, gentamicin, and tobramycin in plasma and in perilymph of guinea pigs were studied after a single intravenous injection of 40 mg/kg. Detailed pharmacokinetic analysis of the plasma drug concentration-time data up to 36 h after the intravenous dose revealed that the pharmacokinetics of the aminoglycoside antibiotics can be best described as a three-compartment open model. The disposition half-lives (t1/2) in plasma of the three antibiotics were comparable and within the following ranges: t1/2 alpha of 0.09 to 0.16 h; t1/2 beta of 0.88 to 1.01 h; and t1/2 gamma of 7.87 to 8.29 h. The volume of distribution in the central compartment and the total body clearance of netilmicin (294 ml/kg, 5.74 ml/min per kg) were greater than those of gentamicin (160 ml/kg, 3.40 ml/min per kg) and tobramycin (204 ml/kg, 4.63 ml/min per kg). Pharmacokinetic analysis of the perilymph drug concentration-time data indicated that all three antibiotics penetrated the perilymph readily, but netilmicin cleared from the perilymph compartment faster than gentamicin and tobramycin. The maximum perilymph drug concentrations were 4.17, 8.05, and 6.78 micrograms/ml and occurred at 1, 2, and 4 h for netilmicin, gentamicin, and tobramycin, respectively. The ratio of area under the curve of perilymph to plasma was lowest for netilmicin (0.27), followed by gentamicin (0.39) and tobramycin (0.57). These results suggest that the differences in pharmacokinetics and concentrations of netilmicin in the perilymph may account for less ototoxic liability of netilmicin compared with gentamicin and tobramycin.
Aminoglycosides↗
Effect of body weight on postnatal development of the proximal small intestine of the rabbit.
The effect of oral intake and body weight on postnatal maturation of the small intestine was examined in infant rabbits with accelerated weight gain. Intestine from immature animals is characterized by large unidirectional Na fluxes, failure of Na absorption to respond to glucose but increased ability to absorb monosaccharides, and an enzyme pattern of high lactase and thymidine kinase and low sucrase. Postnatal development was monitored by measuring Na and glucose transport in short-circuited jejunum and enzyme activities in jejunal mucosa. Accelerated weight gain was achieved in the experimental group by reducing litter size to 3 animals at 24-48 hours of age. Under glucose-free conditions unidirectional Na fluxes were significantly smaller in tissue from the heavier experimental animals compared to controls. The addition of glucose had no effect on Na fluxes in control tissue but significantly increased Na absorption in the experimental group. Unidirectional and net fluxes of 14C-D-glucose were significantly smaller in the heavy experimental animals compared to controls. Isolated villus enterocytes from the experimental group had reduced lactase and thymidine kinase activities. Sucrase activity, which did not differ in isolated cells, was increased in total mucosa from the experimental group. Solute transport and the enzyme profile in jejunum from the heavier experimental suckling rabbits is characteristic of intestinal epithelium from more mature animals, indicating accelerated postnatal maturation. The findings suggest that oral nutrient intake and body weight, rather than chronologic age, act as the physiologic trigger for postnatal maturation of the small intestine.
Aging↗
Antigenic differences between tumor-associated fetal antigens and rat histocompatibility antigens.
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Animals↗
Bioavailability of orally administered propiram fumarate in humans.
Propiram bioavailability was determined in 10 healthy volunteers after a single role administration of 50 mg (base equivalent) of propiram fumarate in tablet or solution dosage from in a randomized crossover design. The plasma drug concentration-time curve revealed a one-compartment open model with first-order absorption kinetics. There were no statistically significant differences (P greater than 0.05) between all of the measured pharmacokinetic parameters obtained from the tablet and the solution with the exception of the absorption lag time (tlag), where the tablet had a significantly longer tlag. The drug given as a tablet or solution was absorbed rapidly after oral administration with an apparent absorption rate constant of 3.7 hr-1 for both dosage forms. The Cmax value (308 ng/ml for the tablet and 342 ng/ml for the solution) was attained at approximately 1 hr after oral administration. The elimination half-life was 5.2 hr for the tablet and 4.4 hr for the solution, and the apparent distribution volume was 2.31 liters/kg for the tablet and 1.94 liters/kg for the solution. Total body clearance was much greater than renal clearance, indicating extensive metabolic clearance for both dosage forms. The study showed that propiram administered as the tablet was bioequivalent to the solution.
Adult↗
Pharmacokinetic study of sisomicin in humans.
Detailed analyses of the pharmacokinetics of sisomicin administered at doses of 25, 50 and 100 mg intravenously and intramuscularly to healthy volunteers established that the drug is handled by a two-compartment open model system with a disposition (elimination) half-life of 2.6 hr. The kinetic estimates over this dose range are linear and independent of dose and were verified by a 60-min infusion experiment in which dose and the maximum serum concentration achieved (5 microgram/ml) were predicted correctly. Sisomicin was rapidly distributed to the tissue compartment, and equilibrium between the central and the tissue compartment was established by 30 min after dosing. Renal clearance (55 ml/min) of sisomicin was about 30% less than total body clearance (78 ml/min). Total urinary excretion of sisomicin during a 24-hr period following drug administration was about 70% of the dose. The disposition kinetics of sisomicin following intramuscular administration are similar to those obtained following rapid intravenous administration. Intramuscular bioavailability of sisomicin for the doses of 25, 50, and 100 mg was greater than 95%. Based on these results, various initial loading infusion doses and maintenance infusion rates were calculated to provide specific desired peak and steady-state serum sisomicin concentrations rapidly. The purpose was not to expose patients to potentially toxic high peak concentrations of drug while maintaining these concentrations during the current therapeutic dosing intervals of 8 to 12 hr.
Biological Availability↗