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Updated: Sep 20, 2026
Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice
Published on: October 27, 2014
Biodistribution, radiation dose estimates, and in vivo Pgp modulation studies of 18F-paclitaxel in nonhuman primates
Karen A Kurdziel1, Dale O Kiesewetter, Richard E Carson
1PET Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA. kurdziel@hsc.vcu.edu
Unlabelled:
Multidrug resistance (MDR) associated with increased expression and function of the P-glycoprotein (Pgp) efflux pump often causes chemotherapeutic failure in cancer. To provide insight into both the dynamics of the pump and the effects of MDR, we radiolabeled paclitaxel, a substrate for the Pgp pump, with (18)F to study MDR in vivo with PET. We obtained biodistribution and radiation dose estimates for (18)F-paclitaxel (FPAC) in monkeys and studied the effects of a Pgp blocker (XR9576, tariquidar) on FPAC kinetics.
Methods:
Paired baseline and Pgp modulation (2 mg/kg XR9576) 4-h whole-body dynamic PET scans were obtained in 3 rhesus monkeys after injection of FPAC. Measured residence times were extrapolated to humans and radiation dose estimates were obtained using MIRDOSE3.1. The postmodulator area under the time-activity curves (AUCs) and Logan plot slopes, a measure of tracer distribution volume (equilibrium tissue-to-plasma ratio) that is inversely proportional to tracer efflux, were compared with baseline values to determine changes in FPAC distribution.
Results:
Cumulative activities of the organs sampled accounted for 80% of the injected dose. The critical organ is gallbladder wall (0.19 mGy/MBq [0.69 rad/mCi]), followed by liver (0.14 mGy/MBq [0.52 rad/mCi]); the effective dose is 0.022 mSv/MBq (0.083 rem/mCi). XR9576 preinfusion changed the Logan plot slope for liver by +104% (P = 0.02), lung by +87% (P = 0.11), and kidney by -14% (P = 0.08). Changes in the mean AUC (normalized to the plasma AUC) were +54% (P = 0.08), +97% (P = 0.04), and -12% (P = 0.02), respectively, for liver, lung, and kidney. No significant difference was found in the metabolite-corrected plasma AUC (normalized to the injected dose) between the baseline and XR9576 modulator studies (P = 0.69).
Conclusion:
Under Radioactive Drug Research Committee guidelines, 266 MBq (7.2 mCi) FPAC can be administered to humans up to 3 times a year. The increase in FPAC accumulation in liver and lung after XR9576 is consistent with Pgp inhibition and demonstrates the potential of FPAC to evaluate MDR.
Insights
This study developed (18)F-paclitaxel (FPAC) for PET imaging to assess P-glycoprotein (Pgp) mediated multidrug resistance (MDR) in cancer. Blocking Pgp with XR9576 increased FPAC accumulation in the liver and lungs, confirming FPAC
Area of Science:
- Nuclear medicine and molecular imaging
- Pharmacology and drug resistance mechanisms
- Oncology and cancer therapeutics
Background:
- Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) efflux pumps is a major cause of chemotherapy failure in cancer.
- Non-invasive imaging methods are needed to understand Pgp function and MDR in vivo.
- Paclitaxel is a Pgp substrate, making it a potential candidate for developing PET imaging agents.
Purpose of the Study:
- To develop and evaluate (18)F-paclitaxel (FPAC) as a positron emission tomography (PET) tracer for studying Pgp-mediated MDR.
- To assess the biodistribution and radiation dose of FPAC in non-human primates.
- To investigate the effect of a Pgp inhibitor (XR9576) on FPAC kinetics and distribution.
Main Methods:
- Radiolabeling of paclitaxel with Fluorine-18 to create FPAC.
- Dynamic whole-body PET scans in rhesus monkeys before and after administration of the Pgp blocker XR9576.
- Analysis of FPAC biodistribution, pharmacokinetic parameters (AUC), and distribution volume (Logan plot slopes) to assess Pgp inhibition.
Main Results:
- The highest radiation dose was estimated for the gallbladder wall (0.19 mGy/MBq) and liver (0.14 mGy/MBq), with an effective dose of 0.022 mSv/MBq.
- XR9576 significantly increased FPAC accumulation in the liver (+104%) and lung (+87%), indicated by higher Logan plot slopes and AUCs.
- Metabolite-corrected plasma AUC did not differ significantly between baseline and Pgp-blocked conditions, suggesting changes were due to tissue uptake.
Conclusions:
- FPAC is a promising PET tracer for evaluating Pgp-mediated MDR in vivo.
- The observed increase in FPAC uptake in liver and lung upon Pgp inhibition confirms the tracer's ability to reflect Pgp function.
- Recommended human dosage of 266 MBq (7.2 mCi) FPAC allows for up to 3 administrations per year under specific guidelines.
