Rabbits clearance

Lidocaine (112), xyloceiine, and dibucaine (113) have been formulated in homo- and copolymers of lactide and glycolide. The goal of these studies has been relatively short-term (24-hr) controlled release of the anesthetic. Injectable microcapsules of lidocaine hydrochloride were produced by an air suspension coating technique and administered i.m. to rabbits (112). Serum levels of Udocaine indicated an initial rise over the first 2 hr and then a gradual decline with clearance after about 8-10 hr. 

Nickel retention in the body of mammals is low. The half-time residence of soluble forms of nickel is several days, with little evidence for tissue accumulation except in the lung (USEPA 1980, 1986). Radionickel-63 (63Ni) injected into rats and rabbits cleared rapidly most (75%) of the injected dose was excreted within 24 to 72 h (USEPA 1980). Nickel clears at different rates from various tissues. In mammals, clearance was fastest from serum, followed by kidney, muscle, stomach, and uterus relatively slow clearance was evident in skin, brain, and especially lung (Kasprzak 1987). The half-time persistence in human lung for insoluble forms of nickel is 330 days (Sevin 1980). 

Schlesinger, R.B., Naumann, B.D., and Chen, L.C., Physiological and histological alterations in the bronchial mucociliary clearance system of rabbits following intermittent oral or nasal inhalation of sulfuric acid mist, J. Toxicol. Environ. Health. 12, 2-3, 441, 1983. 

Hirom [71,72] demonstrated more than three decades ago that the route of excretion of xenobiotics is dependent upon MW by testing up to 75 compounds in rat, guinea-pigs, and rabbits. Lower MW compounds (< 350) were mainly eliminated in the urine (>90%). As MW increased from 350 to 450, a sharp increase in the fraction of compound eliminated in the bile occurred, and for MW > 450, compounds were eliminated 50-100% in the bile in all three species. Smith [73] correlated the log of free metabolic and renal clearance (ml/min/kg) with log D, and found a similar relationship. Metabolic clearance increases with increasing log D, while renal clearance decreases with increasing log D. 

In humans the clearance rate of Hb is higher than that of HpHb (L4, Lll). Murray et al. (M6) found this also to hold for rabbits and, by studying the elimination in nephrectomized animals, they also proved that the difference was not due to urinary loss of Hb. Analysis of the organs proved that the HpHb complex and Hb were assimilated mainly in the liver and were catabolized with an early reappearance of the iron as transferrin iron within 30 minutes. The free Hb accumulated also in the tubular cells of the kidneys. No data have been published suggesting that the spleen is of any appreciable importance in this respect. No typical exponential clearance of the HpHb complex from plasma was observed (L10, Lll) in the first few experiments. Lathem and Worley (L4) found that HpHb disappeared at a simple exponential rate in 5... 

Holma, B. (1967). Lung clearance of mono- and di-disperse aerosols determined by profile scanning and whole body counting A study on normal and S02 exposed rabbits. Acta Med. Scand. (Suppl.) 473 1-102. 

In addition to more rapid absorption of lipids in animals fed casein, another mechanism that may be operative is decreased clearance of circulating lipids. Rabbits fed a casein-based semipurified diet excreted significantly less cholesterol but more bile acids in their feces than animals fed a commercial diet (18). The total sterol excretion in feces of the animals fed the casein diet was half that of the rabbits fed the stock diet. Huff and Carroll (19) found that rabbits fed soy protein had a much faster turnover rate of cholesterol and a significantly reduced rapidly exchangeable cholesterol pool compared with rabbits fed casein. Similar studies performed in our laboratory revealed that the mean transit time for cholesterol was 18.4 days in rabbits fed soy protein, 36.8 days in rabbits fed casein, 33.7 days in rabbits fed soy plus lysine, and 36.3 days in rabbits fed casein plus arginine. These data suggest that addition of lysine to soy protein... 

The extent of drug absorption following nasal administration depends to a reasonable extent on the ease with which a drug molecule crosses the nasal epithelium without degradation or rapid clearance by the mucociliary clearance system. The effects of these two elimination components are more pronounced for proteins and peptides. The nasal administration of drugs, especially proteins and peptides, as well as other molecules has been studied with excised tissues harvested from rabbit, cow, sheep, and pig species (Table 5.2). A... 

Hastings RH, Grady M, Sakuma T, Matthay MA (1992) Clearance of differentsized proteins from alveolar spaces in humans and rabbits. J Appl Physiol 73 1310-1317. 

Involvement of tissue esterases is documented for zomepirac glucuronide, which undergoes rapid hydrolysis in vivo in the guinea pig and rabbit [30], Co-administration of (phenylmethyl)sulfonyl fluoride (an inhibitor of esterases) dramatically decreased the apparent plasma clearance of zomepirac glucuronide, and, in other experiments, strongly increased the apparent plasma clearance of zomepirac administered as such. 

The same liposomal preparation was used to investigate the effect of the administered dose on the biodistribution and pharmacokinetics (41). The effect of the lipid dose of Tc-HYNIC-PEG-liposomes was investigated in the low-dose range (0.02-1.0 pmol/kg), typically for noninvasive imaging applications. The biodistribution and pharmacokinetics of "Tc-HYNIC-PEG-liposomes at various dose levels were studied in rats and rabbits with a focal Escherichia coli infection. Moreover, the pharmacokinetics of Tc-HYNIC-PEG-liposomes at two lipid dose levels were studied in four patients. In rabbits, enhanced clearance was observed at a dose level of 0.02 pmol/kg. The circulatory half-life decreased from 10.4 to 3.5 hours (at 1.0 and 0.02 pmol/kg, respectively). At the lowest dose level, liposomes were mainly taken up by the liver and to a lesser extent by the spleen. Most importantly, the rapid clearance of low-dose PEG liposomes was also observed in humans when relatively low lipid doses were administered as is shown in Figure 4. This study showed that, at very low lipid doses, the biodistribution of PEG liposomes is dramatically altered. 

As observed in Figure 9.4 the intrinsic clearance (as represented by oral unbound clearance CIqu) of UK-147,535 shows an allometric relationship between the rat, dog and man. This would indicate that the transporter protein involved is conserved across these species and has similar affinity. However, marked reduction in clearance in the rabbit suggests the absence, or marked alteration, of the responsible protein in the hepatic sinusoidal membrane of this species. This finding may explain the common observation of reduced biliary excretion of acidic compounds in rabbits compared to other species [24, 25]. 

Fig. 11. Non-invasive in vivo fluorescence time-dependent clearance of ICG from plasma in a rabbit with normal functioning liver. The solid line is a single exponential fit to the measured data...

As shown in rabbits (Table 2), neither Ti/2 nor clearance of the compound were dependent on the injected dose. 

In a second study (Walton et al. 2001b), the magnitude of the interspecies differences in the internal dose of compounds for which glucuronidation is the major pathway of metabolism in either humans or in the test species was determined. There were major interspecies differences in the nature of the biological processes that influence the internal dose including route of metabolism, the extent of pre-systemic metabohsm, and enterohepatic recirculation. There was also a wide variability in the magnitude of differences in the internal dose for all of the test species. The mean values for the clearance ratios compared to humans were 4.5 for the mouse, 9.1 for the rat, 8.7 for the rabbit, and 9.7 for the dog. Thus, the fourfold default factor was exceeded for aU the species. 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

The distribution pattern of intravenously-injected Thorotrast in animals is similar to the pattern in humans most of the Thorotrast is taken up by the RES (Guimaraes et al. 1955 McNeill et al. 1973 Reidel et al. 1979). Reidel et al. (1979) determined that the average percent distribution of Thorotrast in the liver was within one order of magnitude in mice, rats, rabbits, dogs, and humans. The amount of thorium in the spleen of all species, except mice, was clearly below that in humans. Only 50% of the thorium in rats was retained in the liver and spleen, while approximately 85% was retained in humans. Direct comparison of the species is difficult, since the data were taken from other authors and analyzed by Reidel et al. (1979). The study concluded that the biological behavior of colloids was similar in humans and animals. Kaul and Heyder (1972) reported an extremely low rate of clearance of the colloid form from the blood about 1 hour after intravenous injection in rabbits. Subsequently, an increase in the rate of disappearance from the blood of the colloid form (biological half-life of 90 minutes) and of the soluble form (biological half-life of 75 minutes) was found. After 3, 6, or 12 hours, 23, 45, or 60% of the injected amount, respectively, was located in the liver. 

The following experiments arc at variance with such a clearance mechanism. Incubation of rabbit erythrocytes with V. cholerae sialidase in the presence of inhibiting concentrations of Neu2en5Ac protects surface sialic acids and, correspondingly, survival of the cells in circulation.142 Treatment of erythrocytes by V. cholerae sialidase immobilized on Sepharose 4B, allowing complete separation of the enzyme from the cells after incubation, resulted in engulfment of these cells by macrophages at a rate similar to that observed with cells treated with the soluble enzyme. 1 1... 

Oguchi, K., Ikegami, M., Jacobs, H., and Jobe, A. (1985). Clearance of large amounts of natural surfactants and liposomes of dipalmitoylphosphatidylcholine from the lungs of rabbits. Exp. Lung Res., 9, 221-235. 

On the other hand, the volume of disfiibution is significantly increased for orally administered trimethoprim in feverish rabbits compared with their healthy counterparts and absorption is reduced (38). The significance of these changes can be appreciated if one considers that the total body clearance of a drug is... 

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