Biodistribution, radiation dose estimates, and in vivo Pgp modulation studies of 18F-paclitaxel in nonhuman primates.
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).


CONCLUSIONS
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.
Kurdziel
Karen A
KA
PET Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA. kurdziel@hsc.vcu.edu
Kiesewetter
Dale O
DO
Carson
Richard E
RE
Eckelman
William C
WC
Herscovitch
Peter
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005260:Female; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011323:Primates; D011804:Quinolines / Q000493:pharmacokinetics*; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods; D014018:Tissue Distribution; D014915:Whole-Body Counting / Q000379:methods
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; C402343:tariquidar; D017239:Paclitaxel