Biomedical subjects

G R Granneman

Publications and source records attributed to G R Granneman.

At least 55 records · Page 3Linked to original sources

PubMed1995

The effect of mild or moderate hepatic impairment (cirrhosis) on the pharmacokinetics of zileuton.

The pharmacokinetics of zileuton and its R(+) and S(-) glucuronide metabolites were determined after single and multiple (400mg every 8 hours) oral dose administration in healthy subjects (n = 5) and patients with mild or moderate hepatic impairment (cirrhosis; n = 8). The clearance of total zileuton (unbound plus bound to plasma proteins) in patients with hepatic impairment (approximately 350 ml/min) was approximately half than in healthy subjects (approximately 670 ml/min), with similar values in patients with mild or moderate cirrhosis. However, the clearance of unbound zileuton in patients with moderate hepatic impairment was nearly half that in patients with mild hepatic impairment, and one quarter that in healthy subjects. On the basis of these findings, it may be necessary to reduce the dose in patients with impaired hepatic function to maintain levels similar to those in healthy subjects.

Administration, Oral↗

PubMed1995

The effect of food on the pharmacokinetics of zileuton.

The present study was undertaken to assess the effect of food on the pharmacokinetic parameters of zileuton. In a nonblinded crossover study, 18 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of zileuton 600mg in the presence or absence of food consisting of a standardised breakfast on the following morning. The mean zileuton peak plasma concentration (Cmax) increased significantly by 27% after food intake, while the mean area under the plasma concentration versus time curve increased by only 1.4%, a difference that was not statistically significant. The mean time to Cmax was unaffected by the presence of food, as were the other pharmacokinetic parameters assessed. Overall, the results suggest that food has a relatively small effect on the rate of zileuton absorption compared with the fasting state, while the bioavailability of the drug appears to be unaffected. Thus, it is concluded that it is appropriate to administer zileuton with or without food.

Absorption↗

PubMed1995

Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.

A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers. Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations. Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds. Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

Administration, Oral↗

PubMed1995

Effect of zileuton on theophylline pharmacokinetics.

In controlled trials involving asthma patients, zileuton - a selective 5-lipoxygenase inhibitor - has significantly improved pulmonary function and reduced symptoms. Since theophylline is frequently prescribed for asthma, we designed a placebo-controlled randomised crossover trial to examine the influence of zileuton on theophylline pharmacokinetics. 16 healthy adult males were given theophylline (Slo-Phyllin) 200mg 4 times daily for 5 days and either zileuton 800mg twice daily or a matching placebo. After a 15-day washout period, theophylline was resumed and the other study drugs reversed. During coadministration with zileuton, mean peak theophylline levels rose from 12.14 to 20.99 mg/L (p < 0.001), while the apparent plasma clearance dropped from 3.74 to 1.91 L/h (p < 0.001). The time to the peak theophylline concentration was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. 14 volunteers reported 44 mild or moderately severe adverse events, possibly or probably related to coadministration of zileuton, and 8 volunteers reported 8 such events with placebo coadministration. Three volunteers receiving theophylline plus zileuton withdrew from the trial prematurely. Thus, a pharmacokinetic interaction that may produce theophylline toxicity exists between zileuton and theophylline. Accordingly, theophylline dosages in patients receiving zileuton should be adjusted to maintain levels within the therapeutic range. Upon initiation of zileuton, the typical asthma patient may require dosage reductions of one-half, and monitoring of plasma theophylline concentrations is recommended.

Administration, Oral↗

PubMed1995

Lack of pharmacokinetic interaction between zileuton and phenytoin in humans.

A randomised double-blind crossover study was undertaken in 20 healthy adult male volunteers to assess the effects of multiple oral dose administration of zileuton (600mg every 6 hours for 8 days) on the single dose pharmacokinetics of phenytoin 300mg. Serial blood samples were collected up to 72 hours after phenytoin administration and plasma concentrations were determined by high performance liquid chromatography. Pharmacokinetic data were analysed utilising noncompartmental and Michaelis-Menten-based population pharmacokinetic analysis. Zileuton did not significantly alter the peak plasma concentration, time to peak plasma concentration, and area under the plasma concentration-time curve of phenytoin. Moreover, population analysis revealed no significant effect of zileuton on the Michaelis-Menten parameters of phenytoin. Thus, coadministration of multiple doses of zileuton (2.4 g/day) did not significantly affect the single dose pharmacokinetics of phenytoin.

Administration, Oral↗

PubMed1995

Assessment of the pharmacokinetic interaction between zileuton and digoxin in humans.

The effects of coadministration of zileuton on the pharmacokinetic profile of digoxin were investigated in a double-blind placebo-controlled crossover study in 12 healthy male volunteers. During each study phase, the subjects received zileuton 600mg every 6 hours (regimen A) or placebo (regimen B) for 13 days. In addition, all subjects received concomitant digoxin 0.25 mg/day on study days 1 to 11 during both study phases. The study results provide no evidence of any significant overall effect of zileuton on digoxin plasma concentration-time profiles. Although the mean time to reach the maximum plasma concentration for digoxin was significantly shorter after concomitant administration of digoxin and zileuton than after concomitant administration of digoxin and placebo (0.95 vs 1.43 hours), there were no significant differences between the 2 regimens in the values for maximum plasma concentration, area under the plasma concentration-time curve from 0 to 24 hours, elimination half-life, oral clearance, and apparent volume of distribution associated with the terminal phase. Therefore, it is concluded that digoxin and zileuton may be coadministered without risk of clinically relevant effects on the pharmacokinetic profile of digoxin.

Administration, Oral↗

PubMed1995

The influence of multiple oral doses of zileuton on the steady-state pharmacokinetics of sulfasalazine and its metabolites, sulfapyridine and N-acetylsulfapyridine.

The effects of zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebo-controlled study enrolling 14 healthy male volunteers. All subjects received SASP 1 g every 12 hours for 8 days and zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.

Administration, Oral↗

PubMed1995

Pharmacokinetic interactions between zileuton and prednisone.

A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 time daily on the pharmacokinetics of prednisolone after a single 400mg oral dose of prednisone. the effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated. Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t1/2) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance. Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0-6) [from 23 to 20 mg/L/h] and a reduction in tMAX (from 2.3 to 1.7 hours), these results were not considered to be clinically significant. Therefore, it is considered that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.

Administration, Oral↗

PubMed1995

The pharmacokinetic and pharmacodynamic interactions between the 5-lipoxygenase inhibitor zileuton and the cyclo-oxygenase inhibitor naproxen in human volunteers.

The potential pharmacokinetic and pharmacodynamic interactions between zileuton, a 5-lipoxygenase inhibitor, and naproxen, a nonsteroidal anti-inflammatory drug that acts as a cyclo-oxygenase inhibitor, have been investigated in 24 healthy volunteers. Coadministration of these 2 drugs had no effect upon the plasma concentration-time curves of either zileuton (800mg) or naproxen (500mg) when compared with each drug administered alone. Both naproxen plasma concentrations during the elimination phase and area under the plasma concentration-time curve values were statistically significantly raised upon coadministration with zileuton, when compared with naproxen alone. However, these differences in these 2 values were sufficiently small to be of no clinical significance. There is no evidence that the combination of zileuton and naproxen had an effect on leukotriene B4 levels that was different from the inhibitory effect of zileuton alone, or had an effect on serum thromboxane B2 levels that was different from the effect of naproxen alone. Moreover, inhibition of the 5-lipoxygenase pathway by zileuton did not appear to aggravate the gastrointestinal adverse events commonly associated with naproxen administration. It is concluded that zileuton and naproxen may be coadministered with minimal risk of a clinically significant interaction.

Administration, Oral↗

PubMed1994

Pharmacokinetics of valproate after multiple-dose oral and intravenous infusion administration: gastrointestinal-related diurnal variation.

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady-state pharmacokinetics of valproate after multiple 250-mg oral and intravenous infusion doses after an intravenous 750-mg loading dose. Multiple blood samples were collected throughout each 168-hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within-regimen comparisons indicated statistically significant differences for mean steady-state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-versus-time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed-release tablet preparation. Between-regimen steady-state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax (Tmax), Cmax, Cmin, AUC, and total body clearance for respective day-4 dosing intervals, but not for the entire day 4, except for Cmin and Tmax. Mean elimination rate constant and half-life did not significantly differ between the regimens. The regimens were bio-equivalent at steady state, as assessed by 90% confidence intervals (two one-sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation ((Cmax-Cmin)/Caverage). Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady-state plasma concentration-versus-time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 micrograms/mL.

Administration, Oral↗

PubMed1994

Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis.

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1993

High-performance liquid chromatographic method for determination of DN-2327, a novel non-benzodiazepine anxiolytic, and/or its active metabolite in human plasma and urine.

A sensitive and precise high-performance liquid chromatographic procedure has been developed for the determination of a new non-benzodiazepine anxiolytic agent, DN-2327 (I), and its pharmacologically active metabolite, MII (II), in human plasma and urine. Extraction of I, II, and the internal standard from plasma and urine samples were achieved using solid-phase extraction. Separation of the analytes was performed on a reversed-phase C18 column. The effluent was monitored with fluorescence detection at excitation and emission maxima of 328 and 367 nm, respectively. The work-up procedure was reproducible and recovered more than 92% of I and II from either plasma or urine. The chromatographic system for plasma and urine extracts allowed complete resolution of I and II from the internal standard with excellent selectivity. For each analyte, the lower detection limits were 0.1 and 1 ng/ml in plasma and urine, respectively. For each analyte, standard curves were linear in the ranges of 0.1-50 and 1-500 ng/ml in plasma and urine, respectively. The method was highly precise, with coefficients of variation for each analyte in quality controls that were generally below 7 and 5% for plasma and urine samples, respectively. The accuracy of the method was good with the deviations between added and calculated concentrations of each analyte being typically within +/- 10% and +/- 5.6% for plasma and urine samples, respectively. The stability of I and II in standard solutions, plasma and urine samples protected from laboratory light was excellent, with no evidence of degradation after 72 h at room temperature, five months at 4 degrees C, or three months at -20 degrees C.

Animals↗

PubMed1993

Enantioselective determination of DN-2327, a novel non-benzodiazepine anxiolytic, and/or its active metabolite in human plasma and urine using high-performance liquid chromatography.

A new rapid, specific and sensitive reversed-phase HPLC method has been developed for simultaneous measurement of the R- and S-enantiomers of DN-2327 (I), a novel non-benzodiazepine anxiolytic, and those of its pharmacologically active metabolite, MII (II), in human plasma or urine. Extraction of all the enantiomers and internal standard was achieved using solid-phase extraction on C8 columns. Resolution was achieved using a Chiral-AGP column with mobile phase comprising 6.5% (v/v) acetonitrile in 50 mM potassium acetate buffer, pH *q3 3.10, at typical flow-rates of 0.35 ml/min for plasma and 1.0 ml/min for urine assays. Fluorescence detection was employed using excitation and emission maxima of 328 and 367 nm, respectively. Analytes were well resolved and no interfering endogenous peaks were observed either from plasma or urine. Standard curves for urine were linear for concentrations up to 500 ng/ml for R- and S-II, with correlation coefficients higher than 0.994 and limit of quantitation (LOQ) of 1 ng/ml for each enantiomer. The LOQ in plasma was 0.1 ng/ml for each of the four enantiomers. The precision and accuracy of the method for the enantiomers of both I and II were good for plasma and urine with coefficients of variations typically within 10%. The stability of the R- and S-enantiomers of II and I in plasma and those of II in urine was excellent, with no evidence of degradation or interconversion during storage and handling.

Anti-Anxiety Agents↗

PubMed1993

Effect of infusion duration on valproate pharmacokinetics.

The pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single-dose, fasting, four-period, randomized, double-blind, placebo-controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non-compartmental and model-dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetic of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal-phase half-life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration-time curve (AUC; 1877 micrograms.h ml-1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614-1656 micrograms.h ml-1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2-15.1 l) and more rapid tissue equilibration. The alpha-phase rate constant declined from a mean of 5.1 h-1 after the 5 min infusion to a mean of 0.9 h-1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in fu was smaller than the decrease in CL'int, such that the product of fu.CL'int showed a net decrease.

Adolescent↗

PubMed1993

Effect of moderate or severe hepatic impairment on clarithromycin pharmacokinetics.

The pharmacokinetic and safety profiles of clarithromycin (C) and its 14-hydroxy-clarithromycin (HC) metabolite were determined after a multiple-dose oral clarithromycin regimen (250 mg twice daily for five doses) in six healthy subjects and seven patients with moderate or severe hepatic impairment (Pugh grades B and C). Plasma and urine C and HC concentrations were determined using high-performance liquid chromatography. Hepatic impairment resulted in increased harmonic mean C terminal disposition half-life and mean +/- SD C renal clearance (CLR) compared with normal volunteers (5.0 vs. 3.3 hr and 170 +/- 69 vs. 111 +/- 17 mL/min, respectively). Hepatic impairment also resulted in decreased metabolite peak plasma concentration and area under the plasma concentration-versus-time curve and decreased metabolite/parent concentration ratios compared with normal volunteers. These data suggest that 14-hydroxylation of C was reduced by moderate to severe hepatic impairment. No adverse events were noted in either study group and there were no study-related clinically significant changes in laboratory parameters. The decrease in C metabolic clearance appears to be partially offset by an increase in C CLR, resulting in comparable steady-state concentrations of parent drug. In those indications in which the metabolite may be a necessary element of the antimicrobial activity of C, it would seem prudent to be cautious in using C in patients with moderate to severe hepatic impairment due to reduced production of HC. Otherwise, no dosage adjustment for C appears necessary for subjects with moderate or severe hepatic impairment provided that renal function is not impaired.

Chromatography, High Pressure Liquid↗

PubMed1993

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a renin inhibitor). II: A dose-ranging study in patients with congestive heart failure.

This study describes the relationship between the measured effects (the acute effects on systemic hemodynamics and cardiac function) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after i.v. infusion dosing of enalkiren (A-64662) in patients with congestive heart failure. Ascending doses from 0.003 to 1.0 mg/kg were evaluated. Timed blood samples were obtained to measure enalkiren levels in plasma. The plasma level-effect plots showed little or no hysteresis. A sigmoid Emax model was used to develop the relationship between the predicted plasma enalkiren levels and hemodynamic effects. Although hemodynamic effects were observed for most patients, random noise in the dynamics or modest net effects compared to baseline fluctuations precluded simultaneous modeling of the pharmacokinetics and pharmacodynamics for a few patients. While the sensitivity toward enalkiren's effects varied substantially among this group of patients, the studywide estimates of the EC50 for the blood pressure measures averaged about 3,500 ng/ml. The mean EC50 for systolic blood pressure (SBP, 2,744 ng/ml) was lower than those of diastolic blood pressure (DBP, 3,438 ng/ml) and mean arterial pressure (MAP, 3,371 ng/ml), suggesting that the SBP might be a more sensitive measure than the other two.

Adult↗

PubMed1993

Stereoselective pharmacokinetics of pazinaclone, a new non-benzodiazepine anxiolytic, and its active metabolite in healthy subjects.

1. Serum and urine concentrations of enantiomers of pazinaclone (DN-2327) and an active metabolite MII, were measured after single and twice daily oral doses of 4 and 8 mg racemic drug to healthy subjects. 2. The kinetics of rac-pazinaclone and rac-MII were dose-independent and no unchanged drug was recovered in urine. 3. The terminal elimination half-lives of the drug isomers were similar (about 10.5 h), but mean steady-state values of AUC were twofold higher for the S-isomer than those of the antipode (e.g., 8 mg dose: 127 vs 69 ng ml(-1) h). However, the corresponding AUC values based upon unbound drug were similar (5.71 vs 5.73 ng ml(-1) h) indicating no stereoselectivity in intrinsic metabolic clearance. 4. The terminal elimination half-lives of S- and R-MII were similar to those of parent compound indicating that the elimination of these metabolites is formation rate-limited. 5. The R:S-ratio for the AUCs of MII was 4:1. Both enantiomers were excreted in the urine mainly as glucuronide conjugates, with stereoselectivity toward S-MII. 6. Since only the S-enantiomers of DN-2327 and MII bind to the benzodiazepine receptor, further measurements of drug effect in patients should be related to combine serum concentrations of the S-enantiomers of both parent drug and MII.

Administration, Oral↗

PubMed1993

Age-related differences in the pharmacokinetics and pharmacodynamics of lansoprazole.

1. The pharmacokinetics and pharmacodynamics of lansoprazole, an antisecretory and antiulcer agent, were evaluated in 12 older (> 60 years) and 12 younger (< 60 years) healthy men. 2. Doses of lansoprazole (15 or 30 mg) or placebo were each given once daily for 7 consecutive days in this randomized, double-blind, three-way crossover study. Plasma concentrations and urinary excretion of lansoprazole and its metabolites, and gastric acid secretion were monitored after dosing on days 1 and 7 of each treatment period. 3. Within each age group, lansoprazole pharmacokinetics were linear. The mean clearance and elimination half-life of lansoprazole were about 40% lower and higher, respectively, in the older subjects (CL0: 12-14 vs 20-24 1 h(-1); t1/2,z: 1.90-2.19 vs 1.26-1.44 h). 4. At each dose level, acid secretion was more inhibited in the older group. However, the AUC associated with a 50% decrease in acid secretion was similar (849 vs 892 ng ml(-1) h) for both age groups. Multiple dosing decreased the maximum possible inhibition more in the older group than in the younger group. 5. Since the decrease in acid output associated with equivalent AUCs on day 1 was similar for the two age groups, the greater difference between day 1 and day 7 secretion in the older group indicates that recovery of secretory activity may decline with increasing age.

2-Pyridinylmethylsulfinylbenzimidazoles↗