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Biomedical subjects

J R Koup

Publications and source records attributed to J R Koup.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effect of oral activated charcoal on tobramycin clearance.

To evaluate the effect of activated charcoal on aminoglycoside pharmacokinetics, six healthy volunteers received tobramycin intravenously with and without multiple oral doses of activated charcoal. Activated charcoal did not have a statistically significant effect on any pharmacokinetic parameter. We conclude that activated charcoal does not enhance tobramycin clearance in subjects with normal renal function when concentrations in serum are within the therapeutic range.

Administration, Oral↗
PubMed1988

Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans.

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.

Administration, Oral↗
PubMed1988

Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men.

The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.

Adult↗
PubMed1987

Evaluation of a proposed method for phenytoin maintenance dose prediction following an intravenous loading dose.

A large clinical study, designed to investigate the induction of theophylline metabolism by phenytoin, provided the opportunity to test a previously proposed method for estimating dose requirements of phenytoin. This method involves prediction of the oral maintenance dosage from data obtained following the administration of an intravenous loading dose. In 30 subjects, trough plasma concentration at steady-state were 12.0 +/- 4.9 micrograms X ml-1 (mean +/- SD) and differed by -2.7 +/- 39.3% from a mean target plasma concentration of 12.5 +/- 1.5 micrograms X ml-1. A Bayesian regression programme was used to forecast an estimate of each subject's individual pharmacokinetics. These were then used to predict the steady-state plasma concentrations which would be expected from a standard dosing regimen (4 mg per kg per day). When compared to the results expected from the use of this standard dosage, the proposed method gave acceptable steady-state plasma phenytoin concentrations with significant reductions in deviations from target concentrations. This method for the rapid individualization of phenytoin dosage requirements provides an improvement over more traditional methods of choosing an arbitrary dose adjusted for body weight followed by dosage adjustments based on achieved plasma concentration.

Adult↗
PubMed1987

Cigarette smoking and theophylline metabolism: effects of phenytoin.

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 +/- 2.0 micrograms/ml) and smokers (11.5 +/- 0.9 micrograms/ml). Control theophylline elimination half-life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half-life (26.8% +/- 5.6% in smokers and 25.8% +/- 3.5% in nonsmokers) and clearance (48.0% +/- 10.1% in smokers and 39.7% +/- 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.

Adult↗
PubMed1987

Effect of orally administered activated charcoal on vancomycin clearance.

Vancomycin is a narrow-spectrum antibiotic that has concentration-dependent efficacy and toxicity. Recent literature indicates that orally administered activated charcoal can enhance the clearance of intravenously administered drugs. To evaluate the effects of activated charcoal on vancomycin clearance, six healthy male volunteers received vancomycin (1 g) intravenously with and without activated charcoal coadministration. In a randomized crossover sequence, subjects were given 50 g of activated charcoal immediately before the vancomycin infusion was begun and 15 g at 2, 4, 6, and 8 h afterwards, or an equal volume of water. Multiple doses of charcoal did not have a statistically significant effect on any pharmacokinetic parameter for vancomycin. Mean control values +/- standard deviation for vancomycin clearance, elimination half-life, and 24-h urinary recovery were 6.4 +/- 1.0 liters/h, 6.6 +/- 1.5 h, and 856 +/- 116 mg, respectively. Mean values for the same parameters were 6.4 +/- 1.0 liters/h, 6.0 +/- 0.9 h, and 897 +/- 130 mg when activated charcoal was given. We conclude that multiple doses of orally administered activated charcoal do not enhance vancomycin clearance in subjects with normal renal function when serum concentrations are within the therapeutic range. The results of this investigation cannot be extrapolated to patients with toxic vancomycin concentrations or renal dysfunction. The use of activated charcoal in these populations warrants further study.

Administration, Oral↗
PubMed1987

Pharmacokinetics of ciprofloxacin in cystic fibrosis.

We studied the pharmacokinetics of ciprofloxacin in 12 adult males with and 12 adult males without cystic fibrosis (CF). In a randomized crossover sequence, the subjects received 200 mg intravenously or 750 mg orally. With intravenous dosing, subjects also received 651 mg of iothalamate, a marker of glomerular filtration, and 700 mg of antipyrine, an indicator of hepatic oxidative drug metabolism. Pharmacokinetic parameters were determined by model independent methods. In the CF subjects, the ciprofloxacin concentration in serum during the first hour after intravenous administration was higher, and the oral absorption rate was slower. Other parameters did not differ between the groups. Mean concentrations in serum 5 min postinfusion were 3.08 and 2.14 micrograms/ml, and mean peak concentrations after oral dosing were 3.24 and 3.34 micrograms/ml in subjects with and without CF, respectively. Mean values for elimination half-life in all subjects were 4.8 and 5.0 h after intravenous and oral administration, respectively. The mean renal clearances in all subjects after intravenous and oral administration were 19.4 and 14.5 liters/h and accounted for 64 and 47% of the total clearance, respectively. These values were significantly greater than renal iothalamate clearance, indicating that tubular secretion contributed to the renal clearance of ciprofloxacin. A total of 69 and 35.4% of the administered ciprofloxacin was recovered from the urine within 48 h after intravenous and oral administration, respectively. The mean bioavailability was 71.2% and did not differ between the groups. We conclude that similar dosing regimens can be used to treat patients with CF and their normal counterparts.

Administration, Oral↗
PubMed1986

Ceftriaxone pharmacokinetics during peritoneal dialysis.

The purpose of this study was to investigate the pharmacokinetics of intraperitoneally (IP) administered ceftriaxone (CRO) in patients maintained on chronic peritoneal dialysis. A single 2 g dose of CRO was administered IP to six adult patients who did not have peritonitis at the time of study. After a 5 hour dwell, the peritoneal fluid was exchanged with CRO-free fluid. Exchanges were carried out every 4 to 8 h, over a 24- to 28-h period. The peak total plasma CRO concentration was 104 micrograms/ml. An average of 74.1% of the IP dose of CRO was absorbed. Plasma protein binding was nonlinear; mean free fraction ranged from 12.8 to 17.9% at low and high concentrations. Dialysate concentrations at the end of subsequent exchanges ranged from means of 19.9 to 2.9 micrograms/ml. Total CRO clearance from plasma was 10.1 ml X kg-1 X h-1 and the mean terminal t 1/2 was 12.7 h. Dialytic clearance averaged 0.69 ml X kg-1 X h-1, only 6.9% of total clearance. A model which incorporates known characteristics of CRO binding and distribution in anuric patients was used to simulate plasma and peritoneal concentrations of CRO during multiple dose IP drug administration.

Adult↗
PubMed1986

Comparison of single and multiple dose pharmacokinetics of theophylline using stable isotopes.

Theophylline, enriched with the stable isotopes 13C and 15N, was administered intravenously in a dose of 10 mg to 8 healthy men following single (200 mg) and multiple (200 mg 8-hourly for 5 days) oral dose administration of aminophylline. Total plasma clearance, volume of distribution, and half-time determined from the intravenous data were similar, demonstrating that the pharmacokinetics of theophylline after chronic dosing can be predicted from the pharmacokinetics of a single dose. With chronic oral dosing, however, the mean trough concentration was 12% higher at 9 a.m. than at 5 p.m., the end of the dose interval (3.94 +/- 0.55 vs. 3.50 +/- 0.45 micrograms X ml-1). The AUC following oral dosing was 25% higher in the multiple dose study than in the single dose study. Simulation analysis suggested that these results could be explained by diurnal variation in the clearance or absorption rate or a combination of both. Thus, the systemic availability of theophylline measured during a single dosage interval after chronic oral dosing to steady state would be overestimated in comparison with that measured after a single oral dose.

Adult↗
PubMed1986

Application of stable isotope methodology in the evaluation of sustained-release theophylline dosage forms.

We compared the kinetics of a single daily dosage form of theophylline (Theo-24) with the kinetics of a twice daily dosage form (Theo-Dur) while we controlled for intrasubject variation in theophylline clearance by use of stable isotope-labeled intravenous theophylline. The stable isotope methodology allowed correction for changes in patient clearance, which allowed more precise estimates of the bioavailability characteristics of these sustained-release theophylline products.

Biological Availability↗
PubMed1986

Pharmacokinetics of rifampin in children. I. Multiple dose intravenous infusion.

The pharmacokinetics of intravenous rifampin (280 +/- 78 mg/m2) were investigated during multiple dose administration in 12 pediatric patients aged 3 months to 12.8 years. Serum rifampin concentration data were fit to a linear one-compartment model. There was a significant effect of duration of therapy on rifampin clearance (Cl) and half-life (t1/2) (p = 0.027 and p = 0.048, respectively). A mean increase of 52.0% in Cl (3.10-4.72 L/h/m2) and a mean decrease of 27.0% in t1/2 (2.38-1.73 h) were observed when data collected during the first 2 days of therapy were compared with data collected following 8 or more days of therapy. Peak concentrations extrapolated to the end of infusion were 27.0 +/- 8.2 micrograms/ml, and concentrations at 8 h after the dose were only 1.9 +/- 1.5 micrograms/ml. There was no significant effect of duration of therapy on these concentration values. There was no correlation between Cl and age or administered dose. Intrapatient variation in Cl was great, as evidence by the lack of correlation of initial Cl values with subsequent values in individual patients (r = 0.259). It would appear that dosage intervals may need to be shortened from 12 to 8 h during continuous therapy, and that periodic measurement of rifampin concentration may be required.

Age Factors↗
PubMed1986

Pharmacokinetics of rifampin in children. II. Oral bioavailability.

The absolute bioavailability of oral rifampin was determined in 20 pediatric patients. Intravenous doses of rifampin (mean 287 mg/m2) were compared with p.o. doses (mean 324 mg/m2). Serum concentrations of rifampin, 25-O-desacetylrifampicin, and 3-formylrifamycin SV were determined by high performance liquid chromatography. Following a 1/2-h intravenous infusion, serum rifampin concentrations declined in a monoexponential fashion. Pharmacokinetic analysis of the rifampin serum concentration data indicated that only 50 +/- 22% of a freshly prepared p.o. suspension was absorbed. The rifampin elimination half-life following i.v. administration (2.25 +/- 0.64 h) was not different from that observed following p.o. dose administration (2.61 +/- 1.35 h). Peak rifampin concentrations were significantly higher following i.v. administration when corrected to a 300 mg/m2 dose (27.4 vs. 9.1 micrograms/ml, respectively, p less than 0.0001) than after p.o. administration. The peak concentration following a p.o. dose occurred at 2.0 +/- 0.9 h. The ratio of desacetylrifampicin to rifampin areas under the curves were similar for i.v. and p.o. routes of administration (0.23 vs. 0.19), suggesting linear metabolism of rifampin to this metabolite. 3-formylrifamycin SV concentrations were lower than those of desacetylrifampicin and were detectable in less than half of the patients. The results of this study indicate the need for larger p.o. doses when serum concentrations similar to those obtained following intravenous doses are desired.

Administration, Oral↗
PubMed1985

Clinical pharmacology of extended-spectrum penicillins in infants and children.

Compared with previously available penicillins, piperacillin, azlocillin, and mezlocillin have increased activity in vitro against gram-negative bacilli. After intravenous administration of conventional doses (50 to 100 mg/kg) in children, peak concentrations of these drugs are approximately 70 to 350 micrograms/ml. For piperacillin, azlocillin, and mezlocillin, the half-lives during the beta elimination phase (t 1/2 beta) are approximately 0.5 to 0.75, 0.8 to 1.7, and 0.8 to 1.0 hours, respectively. In patients receiving the higher dosage, particularly of azlocillin, the t 1/2 beta may be prolonged by approximately 20%. A total daily dosage of 300 mg/kg or 9 gm/m2 given in four to six divided dosages should produce peak concentrations of approximately 150 micrograms/ml, and concentrations greater than 16 micrograms/ml for at least 2 hours after each administration. Lower daily dosages are needed in neonates, but precise dosage recommendations cannot be made at this time. Only approximately 60% of piperacillin and approximately 45% of azlocillin are eliminated unchanged in the urine; thus only modest dosage reductions are needed in patients with decreased renal function. In children, adverse effects have been infrequent.

Absorption↗
PubMed1985

Pharmacokinetics of three oral formulations of ciprofloxacin.

We compared the absorption of three formulations of ciprofloxacin after oral administration in 18 normal adult male volunteers. Each subject received 500 mg of ciprofloxacin as two 250-mg tablets, one 500-mg tablet, or a solution in a randomized crossover sequence. Pharmacokinetic parameters were determined by model independent methods. Because a solution is considered to be the ideal oral dosage form, the results determined for the tablets were compared to those for the solution. Mean values for the maximum concentration of drug in serum, the time to maximum concentration of drug in serum, and the elimination half-life were 3.23 micrograms/ml, 1.00 h, and 5.04 h, respectively, for the solution. The mean renal clearance of ciprofloxacin was 372 ml/min and accounted for at least 50% of the total clearance. We recovered 44.4, 48.6, and 55.8% of the administered ciprofloxacin from the urine as unchanged drug within 24 h after dosing with the 250-mg tablets, 500-mg tablets, or solution, respectively. The 500-mg tablets were found to be bioequivalent to the solution with regard to all pharmacokinetic parameters. The 250-mg tablet was not bioequivalent to either of the other formulations; the relative bioavailability values were 78.7 and 74.1%, respectively, for the 500-mg tablet and the solution. The clinical significance of this difference in bioavailability is yet to be determined.

Administration, Oral↗
PubMed1985

Erythropoietin kinetics in normal and uremic sheep.

Homologous erythropoietin (Ep)-rich plasma was infused into sheep to determine the kinetics of this hormone in a large animal model. Ep levels after infusion were measured by radioimmunoassay using a sheep standard. Twenty-seven infusions into normal (14), subtotally nephrectomized (11), and anephric (two) animals were analyzed according to a single-compartment model. The volume of distribution was also calculated, and compared with values obtained indirectly from measurement of chromium 51-labeled red blood cells. The data showed that the t1/2 of the infused hormone was approximately 9 hours and was independent of renal function. After multiple infusions, the t1/2 appeared to shorten. The volume of distribution for this hormone corresponded to the plasma volume of the animals. These studies suggest that Ep, if administered to patients with chronic renal failure, could be given infrequently with little dependence on renal function.

Anemia↗
PubMed1984

Pharmacokinetics of ceftriaxone in patients with renal and liver insufficiency and correlations with a physiologic nonlinear protein binding model.

In patients with normal hepatic and renal function, between 30 and 60 percent of administered ceftriaxone is eliminated by nonrenal (biliary) mechanisms. Substantial nonrenal elimination reduces the need for dose adjustments in mild and moderate renal impairment. Minor increases in the biologic half-life (12 hours versus normal of 8 hours) of ceftriaxone have been seen in (functionally) anephric patients with normal extrarenal clearance mechanisms. Anephric patients with decreased nonrenal elimination (additional liver damage) showed a greater increase in biologic half-lives (greater than 15 hours). In patients with various degrees of liver insufficiency (alcoholic fatty liver and cirrhosis with and without ascites), only those with ascites showed significant changes in total drug clearance and volume of distribution. However, these changes in patients with ascites were such that they did not demonstrate significantly different biologic half-lives (9.7 hours versus normal of 8 hours). Simulations of observed concentration versus time data support a physiologic disposition model whereby ceftriaxone, like other cephalosporins, distributes only in plasma and in the extravascular-extracellular (interstitial) fluid and ceftriaxone is saturably bound to albumin in both spaces. All observations in normal subjects and patients were in good agreement with the physiologic disposition model predictions. The consequences of the nonlinear binding behavior of ceftriaxone are such that they favor the administration of ceftriaxone in a large single dose rather than in divided doses. No major drug accumulation is expected in patients with renal or hepatic insufficiency, but anephric patients with a decrease of more than 80 percent in nonrenal elimination will require dose adjustments.

Blister↗