The Respective Roles of CYP3A4 and CYP2D6 in the Metabolism of Pimozide to Established and Novel Metabolites

Data Supplement

• Supplemental Data -

  Supplementary Table 1 - Cone Voltage and Collision Energy for Analysis of Analyte Fragmentation on XEVO-TQD.

  Supplementary Table 2 - Cone Voltage and Collision Energy for Analyte Quantification on XEVO-TQ-XS.

  Supplementary Figure 1 - Daughter ions produced from pimozide (top) and the hydroxypimozide (bottom)
  metabolite(s) suggest the benzimidazolone ring is a site of ring hydroxylation in human liver microsomes isolated
  from a donor genotyped as a CYP2D6 ultra rapid metabolizer (UM) and incubated with 10 μM pimozide.

  Supplementary Figure 2 - SmartCYP predictions for sites of metabolism by CYP2D6. Likelihood of being the principle site of site of oxidation decreases with increasing rank number. 

  Supplementary Figure 3 - Elution of hydroxypimozide isomers and DHPBI with products of CYP3A4-mediated
  metabolism at supratherapeutic concentrations of pimozide. 

  Supplementary Figure 4 - Correlation of CYP2D6 protein abundance and the rate of dextromethorphan O-demethylation to dextrorphan in HLMs isolated from individual donors (n = 7). 

  Supplementary Figure 5 - Correlation of CYP3A4 protein abundance and the rate of pimozide 5-hydroxylation (left)
  and 6-hydroxylation (right) in HLMs isolated from individual donors (n = 7).

  Supplementary Figure 6 - Correlation of CYP3A4 protein abundance and the rate of midazolam 1’-hydroxylation
  (left) and testosterone 6β-hydroxylation (right) in HLMs isolated from individual donors (n = 7).

  Supplementary Figure 7 - Correlation of CYP2D6 protein abundance and the rate of DHPBI formation in HLMs
  isolated from individual donors (n = 7).

  Supplementary Figure 8 - Correlation of CYP3A4 and CYP2D6 protein abundance.