profiling of hepatic clearance pathways of pittsburgh compound b and human liver cytochrome p450 phenotyping分析肝脏清除率通路的匹兹堡化合物b和人类肝脏细胞色素p450表现型.pdfVIP

Van Vlaslaer et al. EJNMMI Research 2013, 3:10 /content/3/1/10 SHORT COMMUNICATION Open Access Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping 1 1 1 2,3 4* Anne Van Vlaslaer , Russell J Mortishire-Smith , Claire Mackie , Xavier Langlois and Mark E Schmidt Abstract Background: 11C-PiB has been developed as a positron-emission tomography (PET) ligand for evaluating fibrillar β- amyloid (Aβ) in the human brain. The ligand is rapidly metabolized, with approximately 10% of intact tracer remaining 30 min after injection. When 11C-PiB is used as a treatment endpoint in intervention studies for Alzheimer’s disease (AD), a concern is whether the clearance of the tracer changes from one scan to the next, increasing within subject variability in the PET signal. Subjects enrolled in AD trials may start or stop medications that inhibit or induce xenobiotic metabolizing enzymes such as the cytochrome P450 (CYP) isozymes. Findings: We conducted CYP phenotyping in recombinantly expressed systems, and in human liver microsomes, to evaluate CYP isozyme contributions to the metabolism of PiB (carrier) and profiled microsomal and hepatocyte incubations for metabolites. The metabolism of PiB appears to be polyzymic, with direct conjugation via UDP- glucuronosyltransferases (UGTs) also occurring. Conclusion: It is unlikely that CYP inhibition or induction will significantly influence the clearance of 11C-PiB. Keywords: Amyloid, Pittsburgh compound B, Drug metabolism, Hepatic clearance, P450 phenotyping Findings A critical issue is the possible changes in clearance of Background