Abstract
During drug development, it is important to predict the activities of multiple metabolic enzymes, not only cytochrome P450 (P450) but also non-P450 enzymes, such as conjugative enzymes and aldehyde oxidase (AO). In this study, we focused on prediction of AO-mediated human metabolism and pharmacokinetics (PK) of 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) (Astellas Pharma Inc.), the development of which was suspended due to extremely low exposure in human, despite good oral bioavailability in rat and dog. We examined species difference in oxidative metabolism of the aminopyrimidine moiety of FK3453, catalyzed by AO, using human-chimeric mice with humanized liver (h-PXB mice) and rat-chimeric mice (r-PXB mice) transplanted with rat hepatocytes. AO activity of h-PXB mouse hepatocytes was higher than that of r-PXB mouse hepatocytes. Moreover, higher concentrations of human-specific AO-generated FK3453 metabolite A-M were detected in urine and feces after administration of FK3453 to h-PXB mice versus r-PXB mice. The total clearance of h-PXB mice was 2-fold higher than that of r-PXB mice. These results agreed reasonably well with the metabolism and PK profiles of FK3453 in human and rat. Our results indicated that h-PXB mice should be helpful for predicting the metabolic profile of drugs in humans, and the use of both h-PXB and r-PXB mice should be helpful for evaluation of species differences of AO metabolic activity.
Footnotes
This work was supported by a Grant-in-Aid for Young Scientists (B) from Japan Society for the Promotion of Science [Grant 22790109].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- PK
- pharmacokinetics
- UGT
- UDP-glucuronosyltransferase
- P450
- cytochrome P450
- AO
- aldehyde oxidase
- FK3453
- 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one
- A-M
- AO-generated metabolite
- SCID
- severe combined immunodeficiency
- h-PXB mice
- chimeric mice with humanized liver
- r-PXB mice
- chimeric mice transplanted with rat hepatocytes
- SD
- Sprague-Dawley
- RI
- replacement index
- h-hepatocytes
- h-PXB mice hepatocytes
- r-hepatocytes
- r-PXB mice hepatocytes
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- PEG400
- polyethylene glycol 400
- HPLC
- high-performance liquid chromatography
- Cmax
- the maximum plasma concentration
- tmax
- the time at which Cmax was achieved
- AUC
- the area under the plasma concentration-time curve
- CLt
- total clearance
- i.v.
- intravenous administration
- CLoral
- oral clearance
- p.o.
- oral administration
- t1/2
- half-life
- F
- the oral bioavailability
- CLint, in vitro
- in vitro intrinsic clearance
- SGX523
- 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline
- RO1
- 6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one.
- Received August 5, 2011.
- Accepted October 7, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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