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

Abstract

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% 6 0.007% dose/g of brain) and adolescent (0.020% 6 0.002% dose/ g) monkeys was 4.1-and 2.5-fold greater, respectively, than uptake in adults (0.0082% 6 0.0007% dose/g). The clearance of brain R-11 C-verapamil uptake in adult monkeys was 0.056 6 0.010 mL/min/g, significantly lower than that in infants (0.11 6 0.04 mL/min/g) and adolescents (0.075 6 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.

Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats

“…This negative correlation between brain distribution of oseltamivir and age-dependent P-gp expression suggests that P-gp level at the BBB is one of the determinants of brain distribution of oseltamivir. Similar results have been found in primates: P-gp level at human BBB increased with age (Daood et al, 2008) and brain distribution of 11 C-oseltamivir in infant rhesus monkeys was higher than that in adults (Takashima et al, 2011). Brain exposure to oseltamivir might be higher in human infants than in adults.…”

Species-Dependent Uptake of Glycylsarcosine but Not Oseltamivir in Pichia pastoris Expressing the Rat, Mouse, and Human Intestinal Peptide Transporter PEPT1

“…The mechanism by which prodrug and active metabolite could enter the brain was uncertain but, at least for Ro 64-0802, may be related to the expression of organic anion transporter 3 on both luminal and abluminal membranes of capillary endothelia. Moreover, a recent positron emission tomography study (Takashima et al, 2011) suggested that age-related developmental changes in Pgp function in the blood-brain barrier, as assessed with R-[…”

Analysis of Neuropsychiatric Adverse Events in Patients Treated with Oseltamivir in Spontaneous Adverse Event Reports

“…12) On the other hand, it has recently been reported that developmental changes in p-glycoprotein function in the blood brain barrier of rhesus monkeys using positron emission tomography (PET) with R-(11) C-oseltamivir, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans. 27) Another group, using PET and autoradiography, radioactivity observed in the brains of infant, juvenile and adult rats after injection of [(11) C] oseltamivir.…”