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Developmental Changes in P-Glycoprotein Function in the Blood-Brain Barrier of Nonhuman Primates: PET Study with R-11C-Verapamil and 11C-Oseltamivir.
MedLine Citation:
PMID:  21571790     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Tadayuki Takashima; Chihiro Yokoyama; Hiroshi Mizuma; Hajime Yamanaka; Yasuhiro Wada; Kayo Onoe; Hiroko Nagata; Shusaku Tazawa; Hisashi Doi; Kazuhiro Takahashi; Masataka Morita; Motomu Kanai; Masakatsu Shibasaki; Hiroyuki Kusuhara; Yuichi Sugiyama; Hirotaka Onoe; Yasuyoshi Watanabe
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-13
Journal Detail:
Title:  Journal of nuclear medicine : official publication, Society of Nuclear Medicine     Volume:  -     ISSN:  1535-5667     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217410     Medline TA:  J Nucl Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
RIKEN Center for Molecular Imaging Science, Chuo-ku, Kobe, Japan; and.
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