A physiologically based pharmacokinetic model was developed to evaluate the kinetics of one of the newest sonographic contrast agents available, FS069 or Optison. This material consists of octafluoropropane gas encapsulated in proteinaceous microspheres, injected intravenously for use as a myocardial contrast agent in humans. This model has six compartments: two lung compartments (alveolar and dead volume), and compartments for the heart, slowly perfused tissue, richly perfused tissue, and gastrointestinal tract. The model was developed to determine the distribution and excretion of the octafluoropropane in the body. Despite the high affinity of octafluoropropane for tissue, the model predicted that nearly 100% of the material would be exhaled from the lungs within 6 min. The model verified the results of a phase I clinical trial with 10 healthy subjects. Ventilation rate was found to play a critical role in the complete excretion of this contrast agent. The physiologically based pharmacokinetic model was a useful tool for evaluating the safety of FS069. This model can be used a basis for developing similar models for other types of contrast agents.
OPTISON, an agent being developed as an intravenous (IV) ultrasound contrast agent, consists of a suspension of octa¯uoro-propane (OFP)-containing albumin microspheres.The distribution and elimination of the albumin component and the elimination kinetics of the OFP component of OPTISON (FS069) were studied in the conscious rat and anesthetized canine models, respectively.Radioiodinated OPTISON at 0.25 ml /kg (average dose 5.4 £ 10 7 DPM/rat) and nonradioactive OPTISON, at dosages of 0.3, 0.6, and 1.0 ml/kg, was administered intravenously to conscious rats or to sodium pentobarbital± anesthetized and ventilated canines, respectively. A separate group of rats was housed in metabolism cages for 24 hours to capture excreted radioactivity. The tissue distribution data for the radiolabeled albumin in rats showed that the 125 I activity recovered in the liver was the highest of all the tissues at each timepoint (peak liver radioactivity at 5 minutes with 50.4% of the dose), suggesting that the major route of uptake and metabolism of the radiolabeled albumin shell and its fragments occurred in the liver. The 125 I activity was excreted in the urine, where most of the recovered radioactivity (58.3%) was found at the end of 24 hours. In the anesthetized canine study, simultaneous venous blood samples and exhaled air samples plus additional exhaled air samples were analyzed by gas chromatography. OFP was rapidly exhaled through the lungs after an IV injection such that a maximum of less than 10% of the total dose appeared in the venous blood samples. Statistical moment analysis showed rapid OFP elimination with mean residence times of 46, 41, and 38 seconds for the three dosages, and mean total recoveries for the exhaled OFP were 111%, 100.5%, and 121.6%, respectively. OFP was rapidly exhaled through the lungs after OPTISON injection with short mean residence times from statistical moment analysis. Exhaled OFP displayed one-compartment model kinetics with a measurable distribution phase in the blood using classical pharmacokinetic modeling. The albumin component appeared to be cleared primarily by the liver and radioactivity was excreted in the urine.
We have studied the asparagine synthetase reaction with regard to the ammonia-dependent production of asparagine. Hydroxylamine was shown to be an alternate substrate for the asparagine synthetase reaction, and some of its kinetic properties were examined. The ammonia-dependent reaction was examined with regard to inhibition by asparagine. It was found that asparagine inhibition was partial competitive with respect to ammonia, regardless of the concentration of aspartate. However, when MgATP was not saturating, the inhibition by asparagine became linear competitive. These results were interpreted to be consistent with a kinetic mechanism for asparagine synthetase where ammonia is bound to the enzyme followed by MgATP causing asparagine release.
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