Compartmental modeling of technetium-99m-labeled teboroxime with dynamic single-photon emission computed tomography: comparison with static thallium-201 in a canine model.

UNLABELLED: Di Bella EVR, Ross SG, Kadrmas DJ, et al. Compartmental modeling of technetium-99m-labeled teboroxime with dynamic single-photon emission computed tomography: Comparison with static thallium-201 in a canine model. Invest Radiol 2001;36:178-185. RATIONALE AND OBJECTIVES: A compartmental modeling approach to deriving kinetic parameters from a time series of single-photon emission computed tomography (SPECT) images of technetium-99m-labeled (99mTc-) teboroxime may have value for semiquantitative assessment of myocardial perfusion. This study investigated the value of the kinetic parameters derived from a two-compartment model of 99mTc-teboroxime for measuring myocardial perfusion and compared it with static thallium-201 (201Tl) uptake and microsphere-measured blood flow in dogs. METHODS: Experiments were successfully conducted in 9 of 11 open-chest dogs. During adenosine stress, a single complete set of projections of 201Tl uptake was acquired. 99mTc-teboroxime was then injected during adenosine stress, and a complete set of projections was acquired every 5.7 seconds for 17 minutes. Resting studies were performed on 4 of the animals. All of the projection sets were reconstructed with an iterative algorithm and incorporated corrections for attenuation and the geometric response of the collimators. Regional kinetic parameters (washin and washout) were determined semiautomatically from the time series of reconstructed 99mTc-teboroxime images and registered with microsphere data. Regional washin estimates were compared with 201Tl intensities and myocardial blood flows determined from microspheres. RESULTS: Optimally scaled 99mTc-teboroxime washin parameters and 201Tl uptakes were correlated with microsphere-determined blood flows (r = 0.91, y = 0. 99x + 0.01, and r = 0.92, y = 0.88x + 0.28, respectively). In six of the studies, the left anterior descending coronary artery was occluded, and stress occluded-to-normal (O/N) ratios were calculated. The O/N ratios were 0.32 +/- 0.17 as determined from microspheres injected with 201Tl and 0.38 +/- 0.29 from microspheres injected with 99mTc-teboroxime (P = NS). The O/N ratios were 0.48 +/- 0.16 for static 201Tl uptake and 0.27 +/- 0.21 for 99mTc-teboroxime washin (P < 0.05). CONCLUSIONS: Both 201Tl uptake and 99mTc-teboroxime kinetic parameters were well correlated with flow. The 99mTc-teboroxime washin parameters offer semiquantitative flow values and provide greater defect contrast than can be obtained with 201Tl uptake values.

An investigation into the effect of input function shape and image acquisition interval on estimates of washin for dynamic cardiac SPECT.

Dynamic cardiac SPECT and PET can be used to measure myocardial perfusion by estimating the kinetic rate constant describing the washing of radioactive-labelled tracers from the blood to the extravascular myocardial tissue. Because of differences in photon statistics and data acquisition techniques, protocols which produce optimal estimates of the washin for dynamic cardiac PET may give suboptimal estimates if applied in dynamic cardiac SPECT. Two important factors in the estimation of washin are the shape of the tracer input function and the image acquisition interval. This study uses computer simulations to investigate the effect of varying the tracer infusion length and image acquisition interval on the bias and variance of estimates of washin obtained with dynamic cardiac SPECT and 99mTc-labelled teboroxime. Bias in parameter estimates can be introduced by aliasing, integration of the time-varying radioactivity by the detector, and detector motion. This bias can be reduced by decreasing the acquisition interval and using a longer-duration input function. However, this results in poor photon statistics, which generate large variance, and can also introduce bias in the estimates of the washin. Our studies indicate that better estimates of the washin are obtained by using an acquisition interval that is of sufficient duration to obtain adequate photon statistics even if this is at the expense of temporal resolution. The increase in bias caused by using a 10 or 20 s acquisition interval instead of a 5 s acquisition interval is minimal when compared with the reduction in variance. Variance in estimates is also reduced by using a sharp input function, resulting in higher peak counts during washin. It is also shown that the variance of estimates of the washin increases generally when faster kinetics are observed. This variance can, however, be reduced by using longer acquisition intervals.

Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies.

1. The effect of dose (100 mg, 250 mg, 500 mg, 750 mg and 1000 mg) on the glucuronidation and sulphation of diflunisal was studied in six healthy volunteers. 2. Total urinary recovery ranged from 78.9 +/- 11.9% to 91.5 +/- 18.7% of the administered dose. Urinary recovery (normalized for total urinary recovery) of diflunisal sulphate (DS) significantly increased with dose from 9.3 +/- 3.7% to 18.1 +/- 4.8%. 3. Normalized urinary recovery for diflunisal phenolic glucuronide (DPG) was unaffected by dose (range: 30.6 +/- 3.8% to 40.6 +/- 6.6%). Normalized urinary recovery for the acyl glucuronide (DAG) significantly decreased from 52.3 +/- 4.6% to 40.2 +/- 3.4% as the dose increased. 4. Total plasma clearance of diflunisal significantly decreased from 14.4 +/- 1.4 ml min-1 to 8.7 +/- 1.4 ml min-1 as the dose increased from 100 mg to 750 mg. A further increase in dose to 1000 mg resulted in an unexplained increase in total plasma clearance to 10.3 +/- 1.8 ml min-1. 5. Dose-dependent plasma clearance of diflunisal was caused mainly by saturation of the formation of DAG, whereas the formation of DS and DPG were relatively unaffected by dose.

Single and multiple dose pharmacokinetics of enteric coated ketoprofen: effect of cimetidine.

The effect of cimetidine on the single and multiple dose pharmacokinetics of enteric coated ketoprofen was studied in 12 healthy volunteers. Each subject completed two 8-day study treatment periods: either ketoprofen alone (100 mg p.o. twice daily), or co-administered with cimetidine (600 mg twice daily). tlag, Cmax, tmax, t1/2, and k for ketoprofen were not significantly different between single and multiple dose administration. AUC of ketoprofen was slightly but significantly larger following multiple (21.2 micrograms.h.ml-1) as compared to single dose administration (19.0 micrograms.h.ml-1). As a result, plasma clearance of ketoprofen was slightly but significantly reduced following multiple dose administration (80.6 ml/min vs 89.3 ml/min). Cimetidine had no effect on the single or multiple dose pharmacokinetics of enteric coated ketoprofen. Total 12-h urinary recovery of ketoprofen (mostly in the form of ketoprofen glucuronide) was 83.5% of the dose following single dose administration and was significantly greater following multiple dose administration (93.1%). Again cimetidine co-administration had no effect on the single and multiple dose urinary recovery. The results of this study show that cimetidine is not affecting the oral pharmacokinetics of enteric coated ketoprofen.

The effect of age on piroxicam disposition in rheumatoid arthritis.

The disposition of piroxicam in 23 patients with rheumatoid arthritis (9 males, 14 females, aged 27-79) was studied over 6 weeks using the standard oral dose of 20 mg daily. Clinical status was monitored using standard methods. The mean piroxicam steady state plasma concentration (Css) averaged 9.2 +/- 4.4 micrograms/ml, the majority of which was highly protein bound (1.4 +/- 0.5% unbound). Total plasma clearance (CL/F) of piroxicam was 1.85 +/- 0.81 ml/min and the half life (t1/2) was 53.0 +/- 24.2 h. There was wide intersubject variability in the kinetics of piroxicam and its major metabolite 5'-hydroxypiroxicam. Piroxicam CL/F, t1/2 and Css were modestly correlated with patient age. Clinical effects did not appear to be related to piroxicam plasma levels.

Piroxicam and 5'-hydroxypiroxicam kinetics following multiple dose administration of piroxicam.

Piroxicam (20 mg once daily) was administered orally to six healthy young volunteers for 15 days. Trough steady-state levels of piroxicam and 5'-hydroxypiroxicam were 5.5 and 1.2 micrograms/ml, respectively. Piroxicam's plasma half-life (54.9 h) was significantly shorter than that of 5'-hydroxypiroxicam (70.5 h). Percent unbound piroxicam and 5'-hydroxypiroxicam in plasma at steady-state averaged 1.10 and 8.07 respectively. An average of 25.2% of the dose was recovered in urine as 5'-hydroxypiroxicam; approximately two-thirds (17.2%) in the form of the glucuronide conjugate. Average steady-state plasma levels (Css) of piroxicam (7.0 micrograms/ml) were significantly higher than predicted from a previously reported single dose study (5.3 micrograms/ml).

Excretion of trazodone in breast milk.

The excretion of breast milk was studied in six lactating women following the oral administration of a single trazodone tablet (50 mg). The milk/plasma ratio of trazodone based on area under the plasma and milk curves was small: 0.142 +/- 0.045 (mean +/- s.d.). Assuming that the babies would drink 500 ml 12 h-1, they would be exposed to less than 0.005 mg kg-1 as compared to 0.77 mg kg-1 for the mothers. It is concluded that exposure of babies to trazodone via breast milk is very small.

Effects of age and sex on piroxicam disposition.

Piroxicam kinetics were studied after a single, oral, 20-mg capsule was taken by 12 young (six women, six men) and 13 elderly (seven women, six men) healthy subjects. Plasma samples were drawn for 216 hr after dosing. Plasma protein binding was studied in vitro by equilibrium dialysis and piroxicam concentrations were measured by HPLC with ultraviolet detection. The apparent volume of distribution was smaller in elderly women (7.8 +/- 0.4 l) than in young men (11.3 +/- 0.3 l) and elderly men (10.8 +/- 0.8 l). There were no such differences when the apparent volume of distribution was normalized for total body weight. There was a strong correlation between total body weight and apparent volume of distribution in all subjects (r = 0.83). Plasma protein binding of piroxicam ranged from 98.90% to 99.54% bound and was not affected by age or sex. Piroxicam body clearance in elderly women (0.026 +/- 0.002 ml/min/kg) was approximately 33% lower than in young women (0.039 +/- 0.003 ml/min/kg). This difference was reflected in different t1/2s of 61.7 and 44.9 hr. Predicted steady-state plasma piroxicam concentrations were 5.7 micrograms/ml in young women, 5.4 micrograms/ml in young men, 5.7 micrograms/ml in elderly men, and 9.3 micrograms/ml in elderly women. The high value in elderly women results from the lower piroxicam body clearance and total body weight. Our data suggest that healthy elderly women eliminate piroxicam at a slower rate than healthy young women. The clinical significance of these data needs to be assessed in patients.