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Effect of Solvents on the Time Dependent Inhibition of CYP3A4 and the Biotransformation of AZD3839 in Human Liver Microsomes and Hepatocytes.


Drug Metab Dispos. 2012 Oct 16;


Authors: Aasa J, Hu Y, Eklund G, Lindgren A, Baranczewski P, Malmquist J, Turek D, Bueters T


Abstract

Time dependent inhibition (TDI) of cytochrome P450 (CYP) is usually studied in human liver microsomes (HLM), by investigating whether the inhibitory potency is increased with increased incubation times. The presented work was initiated due to a discrepancy observed for the CYP3A4 TDI results for a drug candidate compound (AZD3839) from an early screening method, where no TDI was detected compared to a regulatory method, where TDI was detected. We show here that the different solvents present in the respective studies; DMSO (screening method) versus methanol or water (regulatory method), were the reason to the different TDI results. We further demonstrate why DMSO, present at the levels of 0.2% and 0.5% in the incubations, masked the TDI effect. In addition to the TDI experiments performed in HLM, TDI studies with AZD3839 were performed in pooled human hepatocytes (Hhep) from different suppliers, using DMSO, methanol or water. The results from these experiments show no TDI or attenuated TDI effect depending on the supplier. Metabolite identification of the compound dissolved in DMSO, methanol or water, after incubations with the different systems (HLM or Hhep) show different profiles, which may be the reason to the differences in the TDI outcomes. Thorough investigations of the biotransformation of AZD3839 have been performed, in order to find the reactive pathway causing the TDI of CYP3A4, and are presented here. Our findings show that the in vitro risk profile for DDI potential of AZD3839 is very much dependent on the chosen test system and the experimental conditions used.

PMID: 23073735 [PubMed - as supplied by publisher]