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Developmental changes in P-glycoprotein function in the blood-brain barrier of nonhuman primates: PET study with
Tadayuki Takashima1, Chihiro Yokoyama, Hiroshi Mizuma
1RIKEN Center for Molecular Imaging Science, Chuo-ku, Kobe, Japan.
Insights
P-glycoprotein (P-gp) function at the blood-brain barrier (BBB) matures with age in monkeys. This developmental change in P-gp activity influences drug penetration into the brain, potentially explaining differences in drug responses between children and adults.
Area of Science:
- Neuroscience
- Pharmacology
- Radiochemistry
Background:
- P-glycoprotein (P-gp) is a key efflux transporter at the blood-brain barrier (BBB), regulating xenobiotic compound entry into the brain.
- P-gp expression and function exhibit developmental changes, impacting drug disposition in the central nervous system.
- Understanding these developmental changes is crucial for optimizing pediatric drug therapies.
Purpose of the Study:
- To investigate the developmental changes in P-gp function at the BBB in nonhuman primates.
- To evaluate the utility of PET imaging with R-(11)C-verapamil for assessing P-gp function.
- To examine the developmental impact on the brain penetration of (11)C-oseltamivir, a P-gp substrate.
Main Methods:
- Positron Emission Tomography (PET) studies were conducted in infant, adolescent, and adult rhesus monkeys.
- Radiotracers R-(11)C-verapamil and (11)C-oseltamivir were administered, with arterial blood sampling and dynamic PET imaging up to 60 minutes.
- P-gp function was assessed by analyzing tracer uptake and clearance kinetics using integration plots.
Main Results:
- R-(11)C-verapamil brain uptake and retention were significantly higher in infants and adolescents compared to adults, indicating lower P-gp efflux activity.
- Clearance rates of R-(11)C-verapamil from the brain were significantly lower in adults than in infants and adolescents.
- (11)C-oseltamivir demonstrated limited brain penetration in adult monkeys, with clearance rates slightly lower than in younger subjects.
Conclusions:
- P-gp function at the blood-brain barrier undergoes significant developmental maturation in rhesus monkeys.
- These age-related changes in P-gp activity correlate with differences in drug penetration into the brain.
- Findings suggest a potential link between developmental BBB P-gp function and observed variations in drug efficacy and toxicity between pediatric and adult populations.
Unlabelled:
P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood-brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-(11)C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of (11)C-oseltamivir, a substrate for P-gp, was investigated as practical examples.
Methods:
PET studies in infant (age, 9 mo), adolescent (age, 24-27 mo), and adult (age, 5.6-6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-(11)C-verapamil and also with (11)C-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration.
Results:
R-(11)C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-(11)C-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% ± 0.007% dose/g of brain) and adolescent (0.020% ± 0.002% dose/g) monkeys was 4.1- and 2.5-fold greater, respectively, than uptake in adults (0.0082% ± 0.0007% dose/g). The clearance of brain R-(11)C-verapamil uptake in adult monkeys was 0.056 ± 0.010 mL/min/g, significantly lower than that in infants (0.11 ± 0.04 mL/min/g) and adolescents (0.075 ± 0.023 mL/min/g). (11)C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-(11)C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys.
Conclusion:
These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.
