Radiolabeling/radiolabeled pharmacokinetics

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

Peptide-derivatization of radionuclides has been used extensively, the advantages of these systems include their high affinity for the target, low toxicity, small size, hydrophilicity, and favorable pharmacokinetics, in addition to easy synthesis (and radiolabeling) routes. 

The same group reported the simultaneous radiolabeling (with DOTA-anchored 4Cu) and fluorescence studies, coupled with biodistribution in vivo and in vitro (92). It is believed that appropriately functionalized SWNTs can efficiently reach tumor tissues in mice with no apparent toxicity (159). Furthermore, water-solubilised carbon nanotubes are nontoxic when taken up by cells even in high concentration (92). These studies have been complemented by the recent PET imaging of water-soluble 86Y labelled carbon nanotubes in vivo (mice) (160,161), to explore the potential usefulness of carbon nanocarriers as scaffolds for drug delivery. The tissue biodistribution and pharmacokinetics of model DOTA functionalized nanotubes have been explored in vivo (mouse model). MicroPET images indicated accumulation of activity mainly in the kidney, liver, spleen, and to a much less... 

CFC, chlorofluorocarbon DPI, dry-powder inhaler HFA, hydrofluoroalkane MDI, metered-dose inhaler UK, unknown. °Lung delivery from in vivo radiolabel scintigraphy or pharmacokinetic studies. 

Validation of the Model. The Corley model was validated using chloroform data sets from oral (Brown et al. 1974a) and intraperitoneal (Ilett et al. 1973) routes of administration and from human pharmacokinetic studies (Fry et al. 1972). Metabolic rate constants obtained from the gas-uptake experiments were validated by modeling the disposition of radiolabeled chloroform in mice and rats following inhalation of chloroform at much lower doses. For the oral data set, the model accurately predicted the total amounts of chloroform metabolized for both rats and mice. 

For a number of years following the discovery and initial clinical use of vinblastine and vincristine, there was relatively little definitive information about the pharmacokinetics of these compounds. Pharmacokinetic studies were accomplished typically using radiolabeled drugs and procedures that were of limited value in distinguishing parent drugs from putative metabolites. 

Clinical pharmacokinetic investigations with both vinblastine and vincristine have revealed a triexponential elimination pattern. As for preclinical pharmacokinetic studies, early information was obtained by analysis of samples from patients receiving radiolabeled drug, but more recent investigations make use of radioimmunoassays. It should be noted that radioimmunoassays, while very sensitive in terms of detecting drugs, may also measure structurally related drug metabolites, and some caution is needed in interpretation of pharmacokinetic results obtained from such studies. 

In the last decade, a large number of radiolabeled small biomolecules have been studied for their potential as radiopharmaceuticals for diagnosis and radiotherapy of various diseases. This review wiU focus on some fundamental aspects of receptor-based diagnostic radiopharmaceuticals, including radiopharmaceutical design, receptors and receptor imaging, choice of biomolecule, and modification of pharmacokinetics. 

E = 137keV). The accompanying emission of 7-radiation can be used for scintigraphic imaging but also makes patient isolation necessary. The different half-lifes and /3 -energies allow individual therapeutic demands such as the pharmacokinetics of the tracer molecule, the linear energy transfer of the nuclides or the biodistribution and clearance of the radiolabeled drug to be met. The principles of the application of radioactive materials for therapy are summarized in an excellent review. ... 

When a compound undergoes metabolism, the pharmacokinetics of major metabolites, particularly those that have pharmacological activity or are responsible for toxicities, should be examined. A long half-life of a metabolite may result in accumulation long after the concentration of the parent molecule has reached steady state. Much of the evaluation of the pharmacokinetics and the rates and routes of metabolism will be studied in animals using radiolabelled drug, but should be supported by cold assays. 

In the development of most new active substances, it is required to investigate the disposition of the compound and its metabolite(s) and their rates and routes of elimination. This is generally carried out with radiolabelled compound, usually In the United Kingdom, approval of the Administration of Radioactive Substances Advisory Committee (ARSAC) is required for administration of radiolabelled compound to man. The purpose of the submission is to demonstrate that the dose of absorbed radiation is minimised by administration of the lowest dose that is consistent with meeting the objectives of the study. In general, the estimated absorbed radiation dose should be less than 500 xSv, but higher amoimts are permissible if they can be justified. The estimate is based on tissue distribution of radioactivity in animals and the pharmacokinetics in animals and man. 

Identification and pharmacokinetics of major metabolites, often using radiolabelled drug... 

HIV-protease. Examination of radiolabeled succinate 200 [202] provided information on the pharmacokinetic behavior of this water-soluble fullerene. A behavior similar to hydrophobic steroids was found, accompanied by a very low level of acute toxicity and the ability of 200 to penetrate the blood-brain barrier [162,195,199, 200, 203]. 

Prelim inary results of a pharmacokinetic study indicate that rats treated orally with C-isophorone excreted 93% of the radiolabel in the urine, expired air, and feces in 24 hours (Strasser 1988). The majority was found in the urine indicating that isophorone was well absorbed. The wide distribution of... 

After oral administration of radiolabeled tilmicosin to broilers at dosage in tire range 25-450 mg/L in water for 3-5 days, radioactivity was mainly distributed to liver and kidney and, to a lesser extent, to muscle and fat. The parent drug was the main residue in tissues, excreta, and bile, but partly desmethylated, hy-droxylated, reduced, and sulfated metabolites could be also identified. Similar pharmacokinetic characteristics were also observed in cattle, swine, and sheep. In broilers treated with tilmicosin at the recommended dosage, residues of the parent drug in liver were 2.6 ppm at day 3 declining to 0.13 ppm at day 17 residue levels in kidney averaged 0.65 ppm at day 3 and declined via 0.08 ppm on day 10 to below 0.06 ppm thereafter. Residues in muscle, fat, and skin were approximately 0.10 ppm at day 3 and less than 0.014 ppm after day 14. 

When a single dose of radiolabeled sulfadiazine was administered to eels at 7 C (200), highest initial radioactivity was observed in blood, liver, kidney, and skin, with a tendency for accumulation in bile and skin. In another pharmacokinetic study (201) on sea-water rainbow trout fed a combination of sulfadia-zine-trimetlroprim, the elimination process for both sulfadiazine and trimethoprim rapidly reached a point at which only a small but persistent residue was left at 8 C as opposed to 10 C, sulfadiazine was the more potent residue promoter, still being detected at 90 days posttreatment. This was suggested to be a result of the greater binding ability of sulfadiazine as a weak electrolyte. The authors proposed a witlidrawal period for sulfadiazine-trimethoprim of 60 days at water temperatures above 10 C for tabled-size fish, and a prohibition on its use below 10 C for such fish. 

Pharmacokinetic data with radiolabeled melengestrol acetate showed that the parent compound and/or its metabolites are primarily eliminated with the feces (16). At 6 h postdosing, total radioactivity in heifer liver, fat, kidney, and muscle tissues was 9-15 ppb, 7-8 ppb, 1.2-1.8 ppb, and 0.5-1 ppb of melengestrol acetate equivalents, respectively. In fat, most of this radioactivity (80%) was found to be due to the parent drug, while in liver, kidney, and muscle tissues the parent drug represented about 37%, 30%, and 45% of the total residues, respectively. 

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