Blood plasma model predictions for the proposed bone-seeking radiopharmaceutical [(117m)Sn]Sn(IV)-N,N',N'-trimethylenephosphonate-poly(ethyleneimine).

In an attempt to elucidate the in vivo stability of the prospective radiopharmaceutical [(117m)Sn]Sn(IV)-PEI-MP, where PEI-MP stands for N,N',N'-trimethylenephosphonate-polyethyleneimine, glass electrode potentiometry was used to determine the stability constants of the Sn(4+) ion as complexed with a variety of physiological amino acids. In addition, linear free energy relationship (LFER) correlation plots were used to extrapolate the constants of the major blood plasma ligands, based on data from Cu(2+), Pb(2+), and Zn(2+). In so doing, a thermodynamic model of blood plasma was established for Sn(4+) from which the complexation tendencies of Sn(4+) were predicted in the event of the intravenous administration of such a drug. It was found that the Sn(IV)-PEI-MP could succumb to competition by the glutamine amino acid, which forms more stable complex(es), whilst the PEI-MP gets taken up largely by Ca(2+). Also, this study shows the value of the in vitro experiments and modeling performed for radiopharmaceutical research and for attempts to reduce the number of animal experiments.

Biodistribution and pharmacokinetics of variously molecular sized 117mSn(II)-polyethyleneiminomethyl phosphonate complexes in the normal primate model as potential selective therapeutic bone agents.

In the search for a cure for metastatic bone cancer, 117mSn with its conversion electrons and low energy photons both of discrete energies shows little bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalise on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalised with methyl phosphonate groups (PEI-MP) and labelled with 99mTc, has shown selective uptake into bone tumours. Furthermore using speciation calculations it was predicted that the Sn(II)-PEI-MP complex would remain intact in the blood plasma. Because of this positive indication animal experiments were carried out to test this prediction. This paper relates the labelling, biodistribution and pharmacokinetics of various fractions of 117mSn-(II) PEI-MP in the normal primate model, and points to promising therapeutic possibilities.

Effects of hypocalcaemia on blood flow to the ovaries of the sheep.

The objectives of the study were to use sheep as a model to determine whether a reduction in plasma calcium concentration similar to that observed during periods of postpartum subclinical hypocalcaemia in lactating dairy cattle might affect the blood flow to the ovaries. Different levels of hypocalcaemia were induced in each of six, non-pregnant sheep by the slow intravenous infusion of Na2-EDTA. Measurements of blood flow to the ovaries were made before and after the induction of hypocalcaemia, using 113Sn and 46Sc radiolabelled microspheres. As plasma ionized calcium was reduced, there was a significant decline in ovarian blood flow. Ovarian blood flow (percentage of resting) = 0.54 Ca++ (percentage of resting) + 58.4. This model was significant at P < 0.01, with R2 = 0.92. Accordingly, a reduction in plasma ionized calcium of 50% would yield a reduction in ovarian blood flow of 16%.