Lee K.C.,Cornerstone Pharmaceuticals Inc. |
Shorr R.,Cornerstone Pharmaceuticals Inc. |
Rodriguez R.,Cornerstone Pharmaceuticals Inc. |
Maturo C.,Cornerstone Pharmaceuticals Inc. |
And 2 more authors.
Drug Metabolism Letters | Year: 2011
CPI-613 is a novel anti-tumor compound with a mechanism-of-action which appears distinct from the current classes of anti-cancer agents used in the clinic. CPI-613 demonstrates both in vitro and in vivo anti-tumor activity. In vitro metabolic studies using liver S9 were performed which demonstrated that CPI-613 undergoes both phase 1 (oxidation) and phase 2 (glucuronidation) transformations. Its metabolic half-life varied between species and ranged from 8 minutes (Hanford minipig) to 47 minutes (CD-1 mouse). We performed metabolite mass assessments using selected in vitro incubation samples and demonstrated that +16 amu oxidation with and without +176 amu glucuronidation products were generated by human and animal liver S9. LC/MS/MS fragmentation patterns showed that an uncommon sulfoxide metabolite was formed and the O-glucuronidation occurred at the terminal carboxyl moiety. We observed that the +192 amu sulfoxide/glucuronide was generated only in human liver S9 and not by any of the other species tested. Synthetic metabolites were prepared and compared with the enzymatically-generated metabolites. Both the chromatographic retention times and the LC/MS/MS fragmentation patterns were similar, demonstrating that the synthetic metabolites were virtually identical to the S9-generated products. CYP450 reaction phenotyping and inhibition data both suggested that multiple CYP isozymes (2C8 and 3A4, along with minor contributions by 2C9 and 2C19) were involved in CPI-613 metabolism and sulfoxide formation. Plasma samples from human subjects dosed with CPI-613 also contained the sulfoxide ± glucuronide metabolites. These results show that the in vitro- and in vivo-generated phase 1 and phase 2 metabolites were in good agreement. © 2011 Bentham Science Publishers. Source
Korfmacher W.,Sanofi S.A. |
Fitzgerald M.,Sanofi S.A. |
Luo Y.,Sanofi S.A. |
Ho S.,Sanofi S.A. |
And 4 more authors.
Bioanalysis | Year: 2015
Background: Capillary microsampling (CMS) of 8 μl of blood provides a methodology that can be utilized for serial sampling in drug discovery mouse PK studies. © 2015 Future Science Ltd. Source
Hougton R.,Quotient Bioresearch |
Gouty D.,Intertek |
Allinson J.,ICON Development Solutions |
Green R.,Quotient Bioresearch |
And 25 more authors.
Bioanalysis | Year: 2012
The 5th GCC in Barcelona (Spain) and 6th GCC in San Antonio (TX, USA) events provided a unique opportunity for CRO leaders to openly share opinions and perspectives, and to agree upon recommendations on biomarker bioanalytical method validation. © 2012 Future Science Ltd. Source
Tseng E.,Pfizer |
Walsky R.L.,Astrazeneca |
Walsky R.L.,EMD Serono, Inc. |
Luzietti Jr. R.A.,Astrazeneca |
And 7 more authors.
Drug Metabolism and Disposition | Year: 2014
Metabolism by cytochrome P4503A (CYP3A) is the most prevalent clearance pathway for drugs. Designation of metabolism by CYP3A commonly refers to the potential contribution by one or both of two enzymes, CYP3A4 and CYP3A5. The metabolic turnover of 32 drugs known to be largely metabolized by CYP3A was examined in human liver microsomes (HLMs) from CYP3A5 expressers (*1/*1 genotype) and nonexpressers (*3/*3 genotype) in the presence and absence of ketoconazole and CYP3cide (a selective CYP3A4 inactivator) to calculate the contribution of CYP3A5 to metabolism. Drugs with the highest contribution of CYP3A5 included atazanavir, vincristine, midazolam, vardenafil, otenabant, verapamil, and tacrolimus, whereas 17 of the 32 tested showed negligible CYP3A5 contribution. For specific reactions in HLMs from *1/*1 donors, CYP3A5 contributes 55% and 44% to midazolam 1′- and 4-hydroxylation, 16% to testosterone 6βhydroxylation, 56% and 19% to alprazolam 1′- and 4-hydroxylation, 10% to tamoxifen N-demethylation, and 58% to atazanavir p-hydroxylation. Comparison of the in vitro observations to clinical pharmacokinetic data showed only a weak relationship between estimated contribution by CYP3A5 and impact of CYP3A5 genotype on oral clearance, in large part because of the scatter in clinical data and the low numbers of study subjects used in CYP3A5 pharmacogenetics studies. These data should be useful in guiding which drugs should be evaluated for differences in pharmacokinetics and metabolism between subjects expressing CYP3A5 and those who do not express this enzyme. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics. Source
Lowes S.,Quintiles |
Lelacheur R.,Agilux Laboratories |
Shoup R.,AIT Bioscience |
Garofolo F.,Algorithme Pharma Inc. |
And 42 more authors.
Bioanalysis | Year: 2014
The topic of incurred sample stability (ISS) has generated considerable discussion within the bioanalytical community in recent years. The subject was an integral part of the seventh annual Workshop on Recent Issues in Bioanalysis (WRIB) held in Long Beach, CA, USA, in April 2013, and at the Global CRO Council for Bioanalysis (GCC) meeting preceding it. Discussion at both events focused on the use of incurred samples for ISS purposes in light of results from a recent GCC survey completed by member companies. This paper reports the consensus resulting from these discussions and serves as a useful reference for depicting ISS issues and concerns, summarizing the GCC survey results and providing helpful recommendations on ISS in the context of bioanalytical method development and application. © 2014 Future Science Ltd. Source