Biomedical subjects

G R Granneman

Publications and source records attributed to G R Granneman.

At least 73 records · Page 4Linked to original sources

PubMed1992

Pharmacokinetics of temafloxacin in humans after multiple oral doses.

The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects.

Administration, Oral↗

PubMed1992

Pharmacokinetics of temafloxacin after multiple oral administration.

Four multiple dose studies involving 102 healthy volunteers were reviewed to determine the sources of intersubject variability in the pharmacokinetics of temafloxacin. As a result of the preferential distribution of temafloxacin into muscle, liver and kidney compared with adipose tissue, the best anthropometric explanatory variable was found to be lean body mass, rather than total body mass or body surface area. Single dose studies have confirmed that the distribution volume of temafloxacin is smaller in subjects in whom the lean body mass:total body mass ratio is low, notably in females, the elderly, and those with hepatic impairment. Average creatinine clearance for the volunteers included in this analysis was normal (109 +/- 29 ml/min), and renal function was only a marginally significant covariate; however, renal clearance accounts for 60 to 70% of total clearance (CLT) and has been shown to be a major factor in the elderly, as well as in patients with renal or hepatic impairment. Since temafloxacin is partially reabsorbed renally, urine flow rate was found to be a potentially important secondary factor. Overall, the pharmacokinetics of temafloxacin are essentially linear, with steady-state plasma concentrations at trough (Cssmin) and 2h postdose (Css2h) averaging slightly more than 0.5 and 1.0 mg/L per 100mg administered every (q) 12h. For example, mean Cssmin and peak steady-state plasma concentration (Cssmax) values after administration of temafloxacin 600mg q12h were 3.3 +/- 1.1 and 6.2 +/- 1.8 mg/L, respectively. Total apparent clearance (CLT/F) and the terminal elimination half-life (t1/2) averaged 11 L/h (184 ml/min) per 55kg lean body mass and 8.4h, respectively. Considering that the data reviewed came from 4 studies with doses ranging from 100 to 800mg q12h, the intersubject coefficients of variation were low for an orally administered drug, ranging from 15.4% for t1/2, 20.6% for Css2h, 21.2% for CLT/F and 25% for Cssmin.

Administration, Oral↗

PubMed1992

Pharmacokinetics of temafloxacin in patients with liver impairment.

A multicentre study was conducted to determine whether liver impairment would alter the pharmacokinetics of temafloxacin, a new fluoroquinolone antimicrobial agent. 16 patients with cirrhosis and 12 healthy volunteers (the control group) received a single oral 600mg dose of temafloxacin. Blood and urine were sampled at frequent intervals after drug administration and assayed by high performance liquid chromatography. The mean age of patients with liver impairment was greater than that of the control group; they also had a lower creatinine clearance and urine output. There was no difference between the groups in either the peak plasma temafloxacin concentration or the time to reach peak concentration. However, the volume of distribution and elimination rate constant of temafloxacin were significantly lower in the group with liver impairment, as were total temafloxacin clearance, renal clearance, and the ratio of renal:creatinine clearance. Nonrenal clearance was similar in patients and controls. Creatinine clearance and urine output were found to account for most of the intersubject variability in total clearance as determined by multiple linear regression analysis. Because the altered temafloxacin pharmacokinetics appear to be primarily due to impaired renal function, this should be the main determinant of temafloxacin dosage in patients with liver disease.

Adult↗

PubMed1992

Hepatobiliary elimination of temafloxacin.

The biliary excretion of temafloxacin and temafloxacin glucuronide was characterised in this study after administration of a single oral temafloxacin 600mg dose to 8 patients with T-tube drainage of the common bile duct inserted after cholecystectomy or choledochotomy. High performance liquid chromatographic analyses of plasma, urine and bile samples collected during the 72h after temafloxacin administration showed that biliary concentrations of unchanged temafloxacin followed a time-course parallel to plasma concentrations but were 5- to 10-fold higher. Biliary temafloxacin peak concentrations ranged from 18.74 to 64.35 mg/L and time to peak concentrations from 0.71 to 10.23h. Mean hepatobiliary clearance of temafloxacin was 3.10 ml/min (0.19 L/h) when calculated for the unchanged drug and 1.43 ml/min (0.09 L/h) when calculated for its biliary excretion as glucuronic acid conjugates. Patients with higher bile production had markedly higher clearance of both temafloxacin and temafloxacin glucuronide. The elimination time-course of the conjugate in bile generally paralleled those of temafloxacin in bile and plasma, although there was a lag in the rate of appearance of the conjugate in bile. Biliary excretion of unchanged temafloxacin and temafloxacin glucuronide accounted for approximately 2.2 and 1% of the administered dose, respectively. Thus, it appears that hepatobiliary elimination of temafloxacin and its glucuronide acid accounts for only a small fraction of total temafloxacin clearance. Nonetheless, concentrations attained in the bile are far above the minimum inhibitory concentration values of pathogens relevant in biliary tract infections.

Administration, Oral↗

PubMed1992

The effect of food on the bioavailability of temafloxacin. A review of 3 studies.

Temafloxacin is a new fluoroquinolone antibacterial agent. Previous pharmacokinetic studies have shown that the extent of absorption of temafloxacin is independent of dose and that the dispositional pharmacokinetics are linear. The pharmacokinetics of 3 tablet formulations of temafloxacin were investigated in phase I studies in healthy adult volunteers, to determine whether the bioavailability is altered by the presence of food. Results of these studies indicate that the absorption of temafloxacin is slightly enhanced by concomitant administration of food. Thus, special coordination of temafloxacin administration and meals appears to be unnecessary.

Adult↗

PubMed1992

Effects of 2 quinolone antibacterials, temafloxacin and enoxacin, on theophylline pharmacokinetics.

Certain quinolone and naphthyridone antibacterial agents reduce the clearance of theophylline, posing potential clinical risks for patients maintained on this bronchodilator. Whether temafloxacin also affects theophylline pharmacokinetics was assessed in a randomised double-blind 3-way crossover study in 12 healthy volunteers, using placebo and enoxacin as controls. Each volunteer participated in all 3 phases of the study, receiving theophylline plus daily divided doses of temafloxacin 800mg, enoxacin 800mg, or placebo, orally for 7 days. Aminophylline 200mg (containing 146mg theophylline) was given orally twice daily on the first 4 days. On the fifth morning, theophylline 200mg was administered intravenously, and serial blood and urine samples were collected for the following 72h. Coadministration of enoxacin significantly reduced the metabolic clearance of theophylline (approximately 65%). In contrast, during coadministration of temafloxacin, theophylline pharmacokinetics did not differ significantly from those during coadministration of placebo. No clinically significant adverse events occurred; total reported adverse events during enoxacin-theophylline administration (n = 33) were higher than those reported during temafloxacin-theophylline administration (n = 22) and theophylline alone (n = 23). Administration of temafloxacin to patients on long term theophylline therapy appears to be a safe and rational choice when treatment with a broad spectrum antibiotic is indicated.

Administration, Oral↗

PubMed1992

Effect of cimetidine on the pharmacokinetics of temafloxacin.

Cimetidine, a widely prescribed histamine H2-receptor antagonist, is known to interact with a variety of drugs; consequently, it is important to determine its potential for interaction with any new drug. The interaction between cimetidine and a new quinolone, temafloxacin, has been examined in an open randomised 2-period crossover study in 12 healthy adults. Half the volunteers received cimetidine 400mg 3 times daily for 8 days. On day 5, a single temafloxacin 400mg dose was administered. No other drugs were allowed during this period. The other volunteers did not receive cimetidine (or any other drugs) for an 8-day period except for temafloxacin 400mg on day 5. Blood and urine were sampled serially after temafloxacin administration and daily thereafter until the last day of the study. A 2-week washout period preceded crossover. Pharmacokinetic analyses showed that cimetidine did not affect the rate or extent of temafloxacin absorption, as evidenced by unchanged peak plasma concentration, time to peak plasma concentration, and terminal-phase volume of distribution. However, renal and total clearance values for temafloxacin were reduced by 19%, and elimination half-life and area under the concentration vs time curve were increased in the presence of cimetidine. The most likely mechanism underlying these effects is inhibition by cimetidine of tubular secretion of temafloxacin in the kidney. The lack of clinically significant adverse effects and the small magnitude of the reduction in temafloxacin clearance suggest that the interaction is of little clinical consequence.

Administration, Oral↗

PubMed1992

Effect of antacid medication on the pharmacokinetics of temafloxacin.

The effect of an antacid drug (Maalox 70) on the pharmacokinetics of temafloxacin was studied in 12 healthy young volunteers. The study was designed as a randomised open 2-period crossover trial in which temafloxacin was administered alone and with Maalox 70. In both treatments, temafloxacin was administered as a single oral 400mg dose on the morning of day 2. In the antacid regimen, 8 doses of Maalox 70 were administered every 2h on day 1, starting at 8am and ending with the last dose at 10pm; 5 doses were given on day 2, at 2.5 and 1h before administration of temafloxacin and 1, 3 and 5h after the temafloxacin dose. With coadministration of Maalox 70, peak plasma temafloxacin concentrations (Cmax) were reduced to 44.6% (+/- 24.5), and AUC(0-infinity) was reduced to 39.8% (+/- 17.4) of the corresponding values obtained when temafloxacin was given alone. Urinary excretion of temafloxacin was reduced to 46.0% (+/- 13.7) of that observed when temafloxacin was administered alone. Time to peak plasma concentration (tmax = 1.8h) was not affected by antacid administration. Comparable or greater antacid-associated reductions in relative bioavailability have been reported for other quinolones. As with other quinolones, the concurrent administration of temafloxacin and antacids should be avoided.

Adult↗

PubMed1992

Effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine.

A number of quinolone antibacterial agents, particularly enoxacin, pefloxacin, pipemidic acid and ciprofloxacin, are known to decrease the clearance of methylxanthines. The effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine were therefore compared in a 3-way crossover study in 12 healthy young volunteers. Each volunteer received 183mg once-daily doses of caffeine in conjunction with twice-daily placebo, temafloxacin 600mg and ciprofloxacin 750mg in 3 separate phases according to a randomised sequence. A doubling of the area under the plasma concentration-time curve (77.8 vs 31.8 mg/L.h) and terminal-phase half-life (9.7 vs 4.5h) of caffeine were observed in the presence of ciprofloxacin. The magnitude of the reduction in the intrinsic clearance of caffeine produced by ciprofloxacin was greater than that described in the literature for ciprofloxacin and theophylline. This may partly be explained by intertrial differences in dosage and study design. Coadministration of temafloxacin did not have any effect on the pharmacokinetics of caffeine, confirming results of other studies suggesting that this agent does not affect methylxanthine clearance. Accordingly, it appears that restriction of caffeine intake during temafloxacin therapy is not necessary.

Adult↗

PubMed1991

The influence of age on the pharmacokinetics of temafloxacin.

The pharmacokinetics of temafloxacin were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a single 600 mg dose. Groups were balanced with respect to gender distribution. Plasma and urine temafloxacin concentrations were determined using high-performance liquid chromatography. Compared with the young group, mean peak plasma concentration in the elderly was 45% higher, the area under the plasma concentration versus time curve was 70% higher, the terminal elimination half-life was 18% higher, and the apparent beta-phase volume of distribution was 30% lower in the elderly group. Gender differences were small and largely disappeared when data were normalized to body surface area. As the difference in elimination half-life was small, alteration of the usual twice-daily dosage regimen is not necessary in the elderly. However, elderly patients with decreased renal function (creatinine clearance less than 40 mL/min) will need dosage reduction, similar to that recommended for younger patients.

Absorption↗

PubMed1991

High-performance liquid chromatographic procedures for the determination of temafloxacin in biological matrices.

A simple and precise high-performance liquid chromatographic procedure has been developed for the determination of temafloxacin and its trace level metabolites in biological matrices. Plasma samples are ultrafiltered after addition of an internal standard in a displacing reagent containing sodium dodecyl sulfate and acetonitrile. Plasma ultrafiltrates or diluted urines are chromatographed on a reversed-phase analytical column, using an ion-pair chromatographic mobile phase and fluorescence detection. The chromatographic system allows resolution and quantitation of temafloxacin's oxidative metabolites, which collectively account for less than 2% of the administered dose. The mean intra-assay coefficient of variation for determination of temafloxacin concentrations in plasma ranging from 0.05 to 10.0 micrograms/ml was 0.7%. The procedure was implemented at four laboratories for the analysis of over 12,000 samples from clinical studies. Inter-assay coefficients of variation estimated from routine analyses of quality control samples in these studies averaged 4% or lower for concentrations in the 0.15-10 micrograms/ml range. The limit of quantitation of the procedure is approximately 10 ng/ml; inter-assay coefficients of variation at 15 ng/ml averaged under 9%. Calibration curves were reproducible and highly linear, with correlation coefficients typically averaging over 0.9995. An alternative, more complex procedure, involving methylene chloride extraction, which extends the detection limits to below 1 ng/ml, is also described.

Anti-Infective Agents↗

PubMed1991

Temafloxacin pharmacokinetics in subjects with normal and impaired renal function.

The pharmacokinetics of temafloxacin were investigated following oral administration of single 400-mg doses to 6 normal subjects and 18 subjects with various degrees of impaired renal function. Renal impairment did not significantly affect the peak concentration, time to peak concentration, or the nonrenal clearance of temafloxacin. Both renal clearance (CLR) and total apparent clearance (CLT/F, where F represents the fraction of dose absorbed) of temafloxacin were highly correlated with creatinine clearance (CLCR). The regression equations were as follows: CLR = 0.85.CLCR, with R2 = 0.907, and CLT/F = 56.0 + 0.92.CLCR, with R2 = 0.656. The half-life (mean +/- standard deviation) increased from 10.6 +/- 2.4 h in the normal volunteers to 24.6 +/- 7.3 h in the subjects with a CLCR of less than 10 ml/min; the respective CLT/F decreased from 169 +/- 58 to 70 +/- 27 ml/min. Compared with the CLT/F in the subjects with normal renal function, CLT/F was reduced 60% in subjects with a CLCR of less than 40 ml/min, indicating that the dosage should be reduced by at least one-half for patients with comparable impairment. For the subjects on chronic hemodialysis, most of the variability in the nonrenal clearance and the terminal-phase rate constant of temafloxacin was associated with the quantity of calcium carbonate and related medication taken for the treatment of hyperphosphatemia. Supplemental dosage is not required for patients undergoing hemodialysis, since the distribution of temafloxacin in tissue is extensive and the recoveries from 4-h dialysis sessions accounted for less than 10% of the drug present at the start of the dialysis.

Adult↗

PubMed1991

Pharmacokinetics of temafloxacin in humans after single oral doses.

Temafloxacin (A-63004) is a new quinolone antibacterial agent with a broad spectrum of activity against gram-positive and gram-negative aerobes and anaerobes. The pharmacokinetics and metabolism of temafloxacin were determined in healthy volunteers after administration of single oral doses of 100, 200, 400, 600, 800, and 1,000 mg. The corresponding peak concentrations in plasma (mean +/- standard deviation) were 0.98 +/- 0.26, 1.61 +/- 0.57, 2.43 +/- 0.56, 3.87 +/- 0.64, 4.54 +/- 1.03, and 6.67 +/- 0.74 micrograms/ml. The times that elapsed to attain peak levels ranged from 1.25 to 3.5 h. Statistical analyses of parameters related to the extent of absorption and the linearity of the dispositional pharmacokinetics detected no dose-related trends. Study-wide, total clearance (223 ml/min) and renal clearance (125 ml/min) showed low intersubject variability, with coefficients of variation near 20%. The terminal-phase rate constant of 0.090 +/- 0.008 h-1 corresponds to a half-life of 7.7 h. Temafloxacin was excreted mainly in the urine, with 57 +/- 11% of the dose appearing in the urine unchanged. Conjugated temafloxacin, oxidative metabolites, and conjugates thereof were minor components in urine, collectively accounting for 5 to 8% of the dose. Since intravenously dosed dogs eliminated 50% of the dose by nonrenal processes, urinary recoveries approaching two-thirds of the dose in humans were consistent with high, if not quantitative, absorption. Reported adverse events were generally mild, were randomly distributed between temafloxacin- and placebo-treated subjects, and were not dose related.

4-Quinolones↗

PubMed1987

High-performance liquid chromatographic procedures for the determination of difloxacin and its metabolites in biological matrices.

A simple and extremely precise high-performance liquid chromatographic procedure has been developed for the determination of difloxacin and its metabolites in plasma and urine. Work-up of plasma samples entails ultrafiltration after addition of an internal standard in a displacing reagent containing sodium dodecyl sulfate. The ultrafiltrates are directly analyzed using a C18 reversed-phase analytical column, a soap-chromatographic mobile phase, and a fluorescence or ultraviolet detector. The mean intra-assay coefficient of variation for difloxacin over a concentration range of 10 ng/ml to 10 micrograms/ml was 0.5% when fluorescence detection and an internal standard were employed. Inter-assay coefficients of variation were approximately 2%. Recoveries of difloxacin and its metabolites were essentially quantitative and calibration curves were strictly rectilinear.

Anti-Infective Agents↗

PubMed1986

Difloxacin metabolism and pharmacokinetics in humans after single oral doses.

By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.

Administration, Oral↗

PubMed1986

Metabolism of 14C-estazolam in dogs and humans.

14C-Estazolam (2 mg) administered orally to dogs and human subjects was rapidly and completely absorbed with peak plasma levels occurring within one hour. In humans, plasma levels peaked at 103 +/- 18 ng/ml and declined monoexponentially with a half-life of 14 h. The mean concn. of estazolam in dog plasma at 0.5 h was 186 ng/ml. Six metabolites were found in dog plasma at 0.5 and 8 h, whereas only two metabolites were detected in human plasma up to 18 h. Metabolites common to both species were 1-oxo-estazolam (I) and 4-hydroxy-estazolam (IV). Major metabolites in dog and human plasma were free and conjugated 4-hydroxy-estazolam; the concn. were higher in dogs. After five days, 79% and 87% of the administered radioactivity was excreted in dog and human urine, respectively. Faecal excretion accounted for 19% of the dose in dog and 4% in man. Eleven metabolites were found in the 0-72 h urine of dogs and humans; less than 4% dose was excreted unchanged. Four metabolites were identified as: 1-oxo-estazolam (I), 4'-hydroxy-estazolam (II), 4-hydroxy-estazolam (IV) and the benzophenone (VII), as free metabolites and glucuronides. The major metabolite in dog urine was 4-hydroxy-estazolam (20% of the dose), while the predominant metabolite in human urine (17%) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. The metabolism of estazolam is similar in dog and man.

Administration, Oral↗

PubMed1984

Aspects of the metabolism of valproic acid.

The metabolic routes of valproic acid (VPA) were studied by i.p. administration of the mono-unsaturated and hydroxylated metabolites to rats. Conjugation with glucuronic acid was a major metabolic route for VPA and its metabolites. Conjugation with glycine was a minor route for VPA, but was of more importance with the unsaturated metabolites. The hydroxylated metabolites, which were further oxidized to oxo-derivatives and subsequently to the dicarboxylic acids, were not metabolically dehydrated to form unsaturated metabolites. Multiple metabolic pathways, including dehydrogenation, isomerization, hydration, hydroxylation, reduction and epoxidation were inferred from the metabolites obtained after dosage of the unsaturated metabolites. Six dien-VPA metabolites were detected in VPA-treated rats, four of which are present in patients. It was concluded that 3-en-VPA and 4-en-VPA pathways, originating through dehydrogenation, are distinct from the omega- and omega-1-hydroxylation pathways. Enzyme induction from co-administration of phenobarbital caused enhancement of the minor omega-1-oxidation pathway, yet the largest effect on clearance came from increases in glucuronidation. Mitochondrial processes were unaffected, resulting in decreased contribution to the total clearance.

Animals↗

PubMed1982

A very precise high-performance liquid chromatographic procedure for the determination of cefmenoxime, a new cephalosporin antibiotic, in plasma.

A simple and very precise high-performance liquid chromatographic procedure has been developed for the determination of cefmenoxime, a new broad spectrum cephalosporin antibiotic, in plasma. The workup procedure involves ultrafiltration of samples which have been treated with sodium dodecyl sulfate to displace the drug from its binding sites on plasma proteins. The ultrafiltrates are then directly injected into a high-performance liquid chromatographic system utilizing a reversed-phase analytical column, and an ultraviolet spectrophotometric detector. The mean assay coefficient of variation over a concentration range of 0.5-200 micrograms/ml is slightly greater than 1% when either p-nitrobenzoic or p-anisic acid is used as the internal standard. Recoveries of drug are essentially quantitative at all levels investigated; hence the calibration curves are rectilinear from the limit of quantification (about 0.05 microgram/ml) to at least 200 micrograms/ml.

Cefmenoxime↗