Schmidt ME, Mortishire-Smith R, van Vlaslaer A, Christiaens T, Langlois X, Mackie C.
Profiling of hepatic clearance pathways of PIB with cytochrome P450 phenotyping.
Human Amyloid Imaging 2011 Meeting Abstracts. 2011 Jan 15;
Introduction: The clearance of 11C-PIB from plasma during PET studies has been well described. 11C-PIB is rapidly
cleared from blood with 10-20% of unmetabolized tracer remaining 30 minutes after injection. We conducted
cytochrome P450 phenotyping to evaluate their contributions to the metabolism of 11C-PIB and profiled liver
microsomal incubations for metabolites. We wished to explore whether peripheral clearance could be susceptible
to cytochrome P450 inhibition or induction, as may occur over the course of progression studies or treatment
Methods: PIB was incubated up to 1 hour in 5 recombinant human CYPs (rhCYPs, 1A2, 2D6, 2C9, 2C19 and
3A4), and in human liver microsomes (HLM) in the presence/absence of isoform-specific chemical inhibitors. The
amount of parent remaining in each sample was quantitated by LC/ToF-MS, and incubates were profiled for phase
1 metabolites using Metabolynx. The relative contribution of each CYP to metabolism was evaluated on the basis
of turnover in recombinant systems, and reduction in turnover in the presence of inhibitors.
Results: In rhCYPs, all isoforms turn the compound over to some degree (1A2>2D6>2C19>3A4>2C9). The only
observed metabolite was the demethylation product, and appearance of metabolite is related to turnover. LC/UV
data suggested that mass balance was not completely covered by the formation of the desmethyl metabolite.
In HLM, reductions in turnover were only significant for inhibitors of 1A2 and 3A4. In the absence of inhibitors,
there is less desmethyl metabolite at 60 minutes than at 15, suggesting a pathway downstream of demethylation.
Inhibition of 3A4 appears to affect the second step, as does 1A2.
Discussion: Based on these experiments, the data suggest polyzymic metabolism, and clearance of PIB is
unlikely to be significantly altered by introduction of discontinuation of CYP inhibitors or promoters over the course
of serial examinations. In vivo experiments can more fully characterise metabolism of PIB.