Drug Elimination Kinetics Following Subconjunctival Injection Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging
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To determine the elimination rates of subconjunctivally injected model drugs using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Gadolinium-diethylenetriaminopentaacetic acid (Gd-DTPA) and gadolinium-albumin (Gd-albumin) were injected in rabbits. Experiments were performed in vivo and post mortem and injection volumes of 200 and 600 μl were administered. Signal intensity values from MR images were converted to concentration of contrast agent to determine the mass clearance rates from subconjunctival space.
Injection volume did not have a significant effect on clearance rate for both Gd-DTPA and Gd-albumin. The clearance rate of Gd-DTPA in vivo was about nine times faster than that post mortem. The in vivo and post mortem clearance rates of Gd-albumin were not significantly different. The in vivo half-life of Gd-DTPA was about 22 min while that of Gd-albumin was about 5.3 h.
DCE-MRI was used to quantitatively compare the subconjunctival clearance rates of Gd-DTPA and Gd-albumin. Dynamic clearance mechanisms present in vivo significantly reduced the subconjunctival concentration of Gd-DTPA but not Gd-albumin. Lymphatic clearance does not seem to be as significant as clearance by blood, as evidenced by data from Gd-albumin injections. Larger injection volumes may allow for longer retention times and prolonged release of drug.
Key wordsdrug transport barrier magnetic resonance imaging ocular pharmacokinetics subconjunctival injection transscleral drug delivery
The authors thank Dr. Robert L. Dedrick for insightful discussion and Dr. Craig J. Galban for assistance with image analysis. Veterinary technical expertise provided by Mark Lawson and Denise Parker is also gratefully acknowledged.
- 9.D. M. Maurice, and Y. Ota. The kinetics of subconjunctival injections. Jpn. J. Ophthalmol. 22:95–100 (1978).Google Scholar
- 13.E. L. Arrindell, J. C. Wu, M. D. Wolf, S. Nanda, D. P. Han, E. C. Wong, G. W. Abrams, W. F. Mieler, and J. S. Hyde. High-resolution magnetic resonance imaging evaluation of blood–retinal barrier integrity following transscleral diode laser treatment. Arch. Ophthalmol. 113:96–102 (1995).PubMedGoogle Scholar
- 17.S. H. Kim, C. J. Galban, R. J. Lutz, R. L. Dedrick, K. G. Csaky, M. J. Lizak, N. S. Wang, G. Tansey, and M. R. Robinson. Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging. Invest. Ophthalmol. Vis. Sci. 48:808–814 (2007).PubMedCrossRefGoogle Scholar
- 25.S. J. Pain, R. S. Nicholas, R. W. Barber, J. R. Ballinger, A. D. Purushotham, P. S. Mortimer, and A. M. Peters. Quantification of lymphatic function for investigation of lymphedema: depot clearance and rate of appearance of soluble macromolecules in blood. J. Nucl. Med. 43:318–324 (2002).PubMedGoogle Scholar
- 27.R. B. Sund, and J. Schou. The determination of absorption rates from rat muscles: An experimental approach to kinetic descriptions. Acta Pharm. Toxicol. (Copenh). 21:313–325 (1964).Google Scholar