Tissue Distribution of¹²⁵ l-LabeIed Albumin in Rats, and Whole Blood and Exhaled Elimination Kinetics of Octafluoropropane in Anesthetized Canines, Following Intravenous Administration of Optison® (FS069)

Abstract

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.

Preclinical Acute Toxicology Study of Surfactant-Stabilized Ultrasound Contrast Agents in Adult Rats

“…Several groups have described the pharmacokinetics of different commercial ultrasound contrast agents using gas chromatography or radiolabeled microspheres. [32][33][34][35] All found that more than 90% of the gas was exhaled within 24 hours, which is in accordance with subsequent results obtained in humans. 36,37 An extensive toxicology study of a commercial ultrasound contrast agent (Optison; GE Healthcare, Princeton, NJ) was performed by Greener and coworkers.…”

Effect of anesthesia carrier gas on in vivo circulation times of ultrasound microbubble contrast agents in rats

“…If there were still MCAs visibly circulating in the image after 20 minutes, data collection was prolonged to accommodate the longer MCA persistence. Data by Killam et al (38) showed that after Optison injection into canines, the octafluoropropane was eliminated after a mean residence time of 38–46 seconds. As our model clearly shows, PFB rapidly dissolves from the microbubble and is replaced by the blood gases.…”

Preserving enhancement in freeze-dried contrast agent ST68: Examination of excipients

“…PFC’s have been extensively studied for their toxicity profile when injected intravenously. They have been found to have extremely low solubility (Weathersby and Homer 1980, Marshall and Longnecker 1996), to be unreactive and not metabolized in dogs (Killam et al 1999), and to be 100% exhaled within 6 minutes in humans (Hutter et al 1999). To be safely delivered intravenously, UCA should not be larger than 8 µm in order to pass through the lung capillaries and bolus injection volumes are typically between 0.5 to 8 ml, including any saline flush used to generate flow after contrast injection (Bouakaz and de Jong 2007, Lindner 2009).…”