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Journal of Nuclear Medicine : Official... Nov 2015Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. (11)C-laniquidar is a newly developed tracer of...
UNLABELLED
Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. (11)C-laniquidar is a newly developed tracer of P-glycoprotein expression. The aim of this study was to develop a pharmacokinetic model for quantification of (11)C-laniquidar uptake and to assess its test-retest variability.
METHODS
Two (test-retest) dynamic (11)C-laniquidar PET scans were obtained in 8 healthy subjects. Plasma input functions were obtained using online arterial blood sampling with metabolite corrections derived from manual samples. Coregistered T1 MR images were used for region-of-interest definition. Time-activity curves were analyzed using various plasma input compartmental models.
RESULTS
(11)C-laniquidar was metabolized rapidly, with a parent plasma fraction of 50% at 10 min after tracer injection. In addition, the first-pass extraction of (11)C-laniquidar was low. (11)C-laniquidar time-activity curves were best fitted to an irreversible single-tissue compartment (1T1K) model using conventional models. Nevertheless, significantly better fits were obtained using 2 parallel single-tissue compartments, one for parent tracer and the other for labeled metabolites (dual-input model). Robust K1 results were also obtained by fitting the first 5 min of PET data to the 1T1K model, at least when 60-min plasma input data were used. For both models, the test-retest variability of (11)C-laniquidar rate constant for transfer from arterial plasma to tissue (K1) was approximately 19%.
CONCLUSION
The accurate quantification of (11)C-laniquidar kinetics in the brain is hampered by its fast metabolism and the likelihood that labeled metabolites enter the brain. Best fits for the entire 60 min of data were obtained using a dual-input model, accounting for uptake of (11)C-laniquidar and its labeled metabolites. Alternatively, K1 could be obtained from a 5-min scan using a standard 1T1K model. In both cases, the test-retest variability of K1 was approximately 19%.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adult; Benzazepines; Biotransformation; Brain; Carbon Radioisotopes; Female; Healthy Volunteers; Humans; Isotope Labeling; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Quinolines; Radiopharmaceuticals; Reproducibility of Results; Young Adult
PubMed: 26294297
DOI: 10.2967/jnumed.115.157586 -
Cancer Control : Journal of the Moffitt... 2003Multidrug resistance (MDR) is a significant obstacle to providing effective chemotherapy to many patients. Multifactorial in etiology, classic MDR is associated with the... (Review)
Review
BACKGROUND
Multidrug resistance (MDR) is a significant obstacle to providing effective chemotherapy to many patients. Multifactorial in etiology, classic MDR is associated with the overexpression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing.
METHODS
The development of P-gp inhibitors is reviewed, including a discussion of early agents that are no longer being developed and third-generation agents that are currently in clinical trials.
RESULTS
First-generation agents (eg, cyclosporin, verapamil) were limited by unacceptable toxicity, whereas second-generation agents (eg, valspodar, biricodar) had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors (tariquidar XR9576, zosuquidar LY335979, laniquidar R101933, and ONT-093) have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on cytochrome P450 3A4 drug metabolism and no clinically significant drug interactions with common chemotherapy agents.
CONCLUSIONS
Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 12712010
DOI: 10.1177/107327480301000207 -
Journal of Nuclear Medicine : Official... Dec 2013Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain... (Clinical Trial)
Clinical Trial
UNLABELLED
Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain may be caused by overexpression or overactivity of multidrug transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier. Laniquidar, an inhibitor of P-gp, has been labeled with (11)C for use in PET studies of P-gp expression in humans. Given potential interspecies differences in biodistribution, the purpose of this study was to ensure safe use of (11)C-laniquidar by determining the dosimetry of (11)C-laniquidar using whole-body PET studies.
METHODS
Six healthy volunteers were subjected to a series of 10 whole-body PET scans within approximately 70 min. Five blood samples were taken during the series.
RESULTS
High uptake of (11)C-laniquidar was seen in liver, spleen, kidneys, and lung, whereas brain uptake was low. The effective dose for (11)C-laniquidar was 4.76 ± 0.13 and 3.69 ± 0.01 μSv·MBq(-1) for women and men, respectively.
CONCLUSION
Biodistribution and measured effective dose indicate that (11)C-laniquidar is a safe tracer for PET imaging, with a total dose of about 2 mSv for a brain PET/CT protocol.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Benzazepines; Carbon Radioisotopes; Female; Humans; Male; Quinolines; Radiation Dosage; Radioactive Tracers; Radiometry
PubMed: 24092938
DOI: 10.2967/jnumed.113.120857