Poster Session I (PI 1-106)Displayed 8:00 am – 3:00 ... - Nature

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and expression of the GGT-pathway genes Ggt1, Anpep and Ccbl1
was unaffected. KEGG pathway analyses on kidneys from treated
mice revealed that the most significantly altered genes were associated
with the p53 signaling network, including Cdnk1a and Mdm2, both in
wild type mice (P=2.40×10 -11 ) and Oct1/2(-/-) mice (P=1.92×10 -8 ).
The significance of this pathway was confirmed in subsequent experiments
demonstrating that even heterozygosity for a p53-null allele
already resulted in amelioration of cisplatin nephrotoxicity. Furthermore,
administration of pifithrin-α, an inhibitor of p53-dependent transcriptional
activation, decreased cisplatin-induced kidney damage in
Oct1/2(-/-) mice compared to vehicle control.
CONCLUSION: These findings indicate that (i) the p53 pathway
plays a crucial role in response to cisplatin treatment and (ii) clinical
exploration of OCT2 inhibitors may not lead to complete nephroprotection
unless this pathway is simultaneously attacked.
PI-43
CONTRIBUTION OF METABOLISM TO SORAFENIB PHAR-
MACOKINETIC VARIABILITY. E. I. Zimmerman, J. L. Roberts,
L. Li, A. Gibson, J. E. Rubnitz, H. Inaba, S. D. Baker; St. Jude Children’s
Research Hospital, Memphis, TN. E.I. Zimmerman: None.
J.L. Roberts: None. L. Li: None. A. Gibson: None. J.E. Rubnitz:
None. H. Inaba: 6. I will be discussing the following product, which
is not labeled for the use under discussion, or the product is still investigational;
Company/Drug; Bayer Pharmaceuticals/sorafenib, Onyx
Pharmaceuticals/sorafenib. S.D. Baker: None.
BACKGROUND: Sorafenib is a multikinase inhibitor currently
under clinical investigation for the treatment of acute myeloid
leukemia (AML). The purpose of our study was to characterize sorafenib
metabolism in pediatric AML patients and determine the UDPglucuronosyltransferase
(UGT) and cytochrome P450 (CYP) enzymes
involved in sorafenib metabolism.
METHODS: Sorafenib was administered (150 or 200 mg/m 2 twice
daily) and PK sampling was performed at steady-state. Sorafenib
metabolism was assessed in vitro using human liver microsomes and
recombinant UGT and CYP isozymes. The effect of azole antifungals
on sorafenib metabolism by UGT1A9 and CYP3A4 was determined
in vitro. Sorafenib and metabolites were measured in human plasma
and in vitro metabolic reaction mixtures by LC-MS/MS.
RESULTS: In 22 children with AML (14 males; median age, 9 yr
[range, 1-17 yr]), the median (range) conversion rate of sorafenib to
sorafenib N-oxide, an active metabolite, was 20% (5.2%-69%). Notably,
metabolism to N-oxide was highest (> 30%) in males aged 5-10 yr.
Sorafenib was predominantly metabolized by UGT1A9 to sorafenib
glucuronide (Km = 3.6 μM) and by CYP3A4 to the N-oxide (Km =
12 μM, Vmax = 3.1 nmol/min/nmol). Ketoconazole inhibited sorafenib
metabolism by UGT1A9 (Ki = 2.2 μM), while ketoconazole, posaconazole
and voriconazole inhibited CYP3A4-mediated metabolism
(Ki = 0.17, 0.38, and 39 μM, respectively). Patients receiving concurrent
voriconazole or posaconazole had the lowest sorafenib N-oxide
conversion rates to the N-oxide (