Pharmacokinetic modeling of motexafin gadolinium disposition in mouse tissues using optical pharmacokinetic system measurements.
Clinical use of radio- or photo-sensitizing agents in anti-cancer treatments may be limited by patient specific variability in the pharmacokinetics (PK) of the sensitizing compound. Previously, our group reported motexafin gadolinium (MGd) concentrations in mouse tissues measured noninvasively by the optical pharmacokinetic system (OPS) in vivo, nondestructively by OPS in situ, and destructively by HPLC ex vivo. This study utilized those reported data to develop compartmental PK models of MGd disposition in plasma, tumor, and skin. The model predicted both the rapid initial distribution and slow elimination phases of MGd in plasma, the fast transport of MGd out of the skin (with no MGd detectable after 120 min), and MGd retention at long times in the tumor (with detectable MGd at 24 h). The same compartmental structure was used to model MGd concentrations vs. time as measured by OPS in situ and HPLC ex vivo. In vivo tumor MGd concentrations measured using OPS were estimated by a linear combination of the model predicted PK profiles in plasma and tumor tissue, which suggests that tissue-specific PK knowledge may be needed in order to interpret volume-averaged optical measurements in vivo. The PK modeling techniques presented here are extensible to other optically active compounds and, potentially, to the development of patient-specific treatment schedules.
Department of Chemical Engineering, University of Pittsburgh School of Engineering, Pittsburgh, PA 15261, USA.
Stephen C
SC
Kanick
Julie L
JL
Eiseman
Robert S
RS
Parker
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D003198:Computer Simulation; D054459:Elasticity Imaging Techniques / Q000379:methods*; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008657:Metabolic Clearance Rate; D008665:Metalloporphyrins / Q000097:blood* / Q000493:pharmacokinetics*; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D017319:Photosensitizing Agents / Q000097:blood / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism*; D014018:Tissue Distribution
D008665:Metalloporphyrins; D017319:Photosensitizing Agents; C437683:motexafin gadolinium