Distribution of TmDOTP^5- in rat tissues: TmDOTP^5- vs. CoEDTA^- as markers of extracellular tissue space

The distribution of TmDOTP^5- in rat tissue was compared with CoEDTA^- , an anionic complex previously used as a marker of extracellular space. Heart, liver, muscle, blood, and urine were collected from rats after infusion of either complex and were quantitatively analyzed by atomic absorption spectroscopy. Although total TmDOTP^5- in blood and tissue was consistently lower (0.88 ± 0.04; n = 6) than CoEDTA^- after an identical infusion protocol (presumably because of some association of the phosphonate complex with bone), a comparison of blood and tissue contents indicated that the two anionic complexes distributed into identical extracellular spaces. Relative extracellular space in the in vivo liver, as determined by TmDOTP^5- and CoEDTA^-, was 0.18 ± 0.02 and 0.15 ± 0.01, respectively. The corresponding relative extracellular space values for the in vivo heart reported by the two agents were identical (0.11 ± 0.02). Experiments were also performed to evaluate the washout kinetics of TmDOTP^5- from anesthesized rats. In rats given a total dose of 0.16 mmol TmDOTP^5-, 81% appeared in urine by 180 min, <2% was found in all remaining soft tissue, leaving ~18% undetected. The rate of Tm appearance in urine was fit to a standard pharmacokinetic model that included four tissue compartments: plasma, one fast equilbrating space, one slow equilibrating space, and one very slow equilibrating space (presumably bone). The best fit result suggests that the highly charged TmDOTP^5- complex is cleared from plasma more rapidly than is the typical lower charged Gd-based contrast agents and that release from bone is slow compared with renal clearance.