On the Safety of 5-[¹²⁵I]IODO-2'-Deoxyuridlne: Preclinical evaluation in swine

Abstract

To increase tumor incorporation and minimize hepatic degradation of radio-IUdR, compartmental administration routes are being considered as an alternative to intravenous (i.v.) injections. Although there are significant data on the biodistribution and some reports on radiotoxicity of i.v.-administered 125IUdR, similar results for other routes of delivery are not available. We have undertaken a series of experiments intended to examine radiation effects of 125IUdR after intravesical (3 swine; eight 3 mCi doses at 4-day intervals), intracarotid (3 swine; two 10 mCi doses at 2-week intervals), and intra-aortic (5 swine, single dose of 10 mCi) administration in a swine model. Liver, renal functions, and complete blood counts were monitored throughout the duration of the experiment. Pharmacokinetics, systemic distribution of radioactivity and metabolites were measured. The normal tissue 125IUdR uptake and histology were determined after necropsy. No adverse systemic effects were identified. Clinical observations, laboratory data, and necropsy results were within normal range.

Norepinephrine-Transporter-Targeted and DNA-Co-Targeted Theranostic Guanidines

“…First, we were able to compare the stability in two sera having comparable levels of nonspecific esterases but lacking carboxylesterase EC 3.1.1.1. And second, we intend to use juvenile pigs as the animal model in preclinical safety studies. − Pigs have many physiological similarities to humans. , Their tissue volumes are comparable to humans, and so the assessment of radiation effects in clinically relevant volumes and more realistic estimates of the radionuclide biodistribution and absorbed radiation doses to normal organs are possible. ,, Compound 21 is slowly processed in human serum to 125 IUdR monophosphate with a half-life of ∼15 h (Supporting Information pp S78, S79). A similar degradation pathway is observed during the cellular processing of 21 .…”

“…The production of 125 IUdR as a common catabolite of new radioactive guanidines is considered a positive outcome. Preclinical and clinical studies established that radioiodinated IUdR undergoes rapid hepatic degradation and has a half-life in the systemic circulation of ∼10 min, ensuring minimal normal tissue exposure to radiation, especially important in pediatric subjects. , …”

“…43,44 Their tissue volumes are comparable to humans, and so the assessment of radiation effects in clinically relevant volumes and more realistic estimates of the radionuclide biodistribution and absorbed radiation doses to normal organs are possible. 43,45,46 Compound 21 is slowly processed in human serum to 125 IUdR monophosphate with a half-life of ∼15 h (Supporting Information pp S78, S79). A similar degradation pathway is observed during the cellular processing of 21.…”

“…Preclinical and clinical studies established that radioiodinated IUdR undergoes rapid hepatic degradation and has a half-life in the systemic circulation of ∼10 min, ensuring minimal normal tissue exposure to radiation, especially important in pediatric subjects. 43,49 Cellular Uptake. All new guanidines have pK a ∼ 12 (Table 2) and are protonated at physiological pH similar to MIBG, which exists as a monocation over a broad pH range resulting in a poor cell membrane permeability that hinders cellular uptake by passive diffusion.…”