Currently available tools for in vitro prediction of fm for P450 and non-P450 enzymes

EnzymeTools available for RAF or ISEFChemical Inhibitorsfm Measurement(from in vitro studies)Clinical Victim DDI Risk*
Recombinant EnzymeProbe metabolic pathwayTissue abundance(Reported example of victim drug)
P450Yes (various)YesaYesaYesaQuantitativeHigh (terfenadine, astemizole, cisapride)
FMOYes (1, 3, 5)YesbYescYesbQualitativeLow
AO/XOLimitedYesdEmergingeYesdQualitativeModerate (allopurinol-XO)
MAOYes (A and B)YesdNoYesdQualitativeLow
UGTYes (various)YesfEmerginggYeshQuantitativefModerate (morphine, zidovudine, lorazepam, mycophenolate mofetil)
SULTYes (various)LimitediEmergingjYesbQualitativeLow
NATYes (1 and 2)YeskNoYeskQualitativeModerate (isoniazid)
GSTYes (various)NoEmerginglYesbQualitativeLow
CESYes (1 and 2)YesnEmergingnYesnQualitativeLow
  • RAF, relative activity factor; ISEF, intersystem extrapolation factor; DDI, drug-drug interaction; P450, cytochrome P450; FMO, flavin-containing monooxygenase; AO/XO, aldehyde oxidase/xanthine oxidase; MAO, monoamine oxidase; UGT, uridine diphosphoglucuronosyltransferase; SULT, sulfotransferase; NAT, N-acetyl transferase; GST, glutathione S-transferase; CES, carboxylesterase

  • * High, several reported; Moderate, rare/occasional reported; Low, none reported

  • a For major isoforms (Table 1).

  • b Nonisoform selective (Table 1).

  • c mRNA-based abundance reported (Identification of Flavin-Containing Monooxygenases FMO 1, 3, 5).

  • d Table 1.

  • e In liver (Estimating Fractional Contribution of Aldehyde Oxidase/Xanthine Oxidase).

  • f For some isoforms, e.g., 1A1, 1A4, 1A6, 1A9, 2B7 (UGT Section and Table 1).

  • g For some isoforms e.g., 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, 2B17 in liver, intestine, and kidney (Determination of Fractional Metabolism by Uridine 5′-diphospho-Glucuronosyltransferase).

  • h For some isoforms e.g., 1A1/3, 1A4, 1A6, 1A9, 2B7 (UGT section and Table 1).

  • i Limited (Table 1).

  • j mRNA-based for 1A1, 1A3/4, 1B1, 1E1, 2A1 in liver, intestine, kidney, lung (Estimating Relative Contribution of Sulfotransferases).

  • k Limited reports (Identifying Role of N-acetyltransferases NAT1 and NAT2) (Table 1).

  • l Limited report -GSTA1, A2, M1, M2, M3, and P1 (Relative Contribution of Glutathione-S-Transferases).

  • m Table 1.

  • n Limited reports (Determining Relative Role of Carboxylesterase CES1 and CES2) (Table 1).