Developmental Changes in P-Glycoprotein Function in the Blood-Brain Barrier of Nonhuman Primates: PET Study with R-^sup 11^C- Verapamil and ^sup 11^C-Oseltamivir

摘要

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-^sup 11^C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of ^sup 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-^sup 11^C-verapamil and also with ^sup 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-^sup 11^C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-^sup 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-^sup 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). ^sup 11^C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-^sup 11^C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightiy 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. [PUBLICATION ABSTRACT] Show less