Table 1.
Effects of common phase I metabolic reactions on the mass-spectrometric behavior and retention in comparison with the parent drug
| Nominal mass shift (ΔDa) | Metabolic reaction (elemental composition change) | Exact mass shift (mDa) | Examples of relative retention shifta | References |
|---|---|---|---|---|
| – | Azo reduction to amines (R1N = NR2 to R1NH2 + R2NH2) | – | – | [145] |
| –14xb | Hydrolysis of esters to carboxylic acid (-CxH2x) | –15.7x | – | [106] |
| –90 | Reductive debenzylation (-C7H6) | –47.0 | 0.74 [134] | [134] |
| –78 | Reductive debromination (-Br+H) | +89.5 | – | [113] |
| –74 | Oxidative debenzylation (-C7H6+O) | –52.0 | – | [180] |
| –68 | Loss of CF3 (-CF3+H) | +12.6 | – | [107] |
| –62 | Oxidative debromination (-Br+OH) | +84.4 | 0.39 [17] | [17] |
| –56 | Debutylation (-C4H8) | –62.6 | – | [107] |
| –45 | Hydrolysis of nitrate to alcohol (-NO2+H) | +14.9 | – | [113] |
| Reductive loss of nitro group (-NO2+H) | +14.9 | 1.37 [46] | [46, 106] | |
| –44 | Decarboxylation (-CO2) | +10.2 | – | [106] |
| –42 | Depropylation (-C3H6) | –47.0 | 0.73—isopropyl [131]; 0.85, 1.09—propyl [24] | [24, 131] |
| –36 | Loss of HCl (-HCl) | +23.3 | – | [148] |
| –34 | Reductive dechlorination (-Cl+H) | +39.0 | – | [148] |
| –30 | Nitro reduction to amine (-O2+H2) | +25.8 | 0.75 [144] | [144] |
| –28 | Deethylation (-C2H4) | –31.3 | 0.87 [76] | [76] |
| –25 | Reductive loss of nitrile group (-CN+H) | +4.8 | 0.88 [45] | [45, 106] |
| –18 | Alcohol dehydration (-H2O) | +10.6 | 2.08c [17] | [17] |
| Oxidative dechlorination (-Cl+OH) | +33.9 | 0.73 [146] | [146] | |
| Reductive defluorination (-F+H) | +9.4 | – | [147] | |
| –16 | Desulfuration (-S+O) | +22.8 | 0.54 [68] | [68] |
| Reduction of sulfoxide to thioether (-O) | +5.1 | – | [113] | |
| Reduction of hydroxylamine to amine (-O) | +5.1 | – | [113] | |
| –14 | O-demethylation (-CH2) | –15.7 | 0.88, 0.93 [19]; 0.56, 0.64 [40]; 0.59 [129]; 0.87, 0.88, 0.90 [130] | [19, 25, 40, 46, 108, 129–131] |
| N-demethylation (-CH2) | –15.7 | 0.82 [52]; 0.84 [135]; 0.87 [51]; 0.88 [19]; 0.90 [40]; 0.92 [133]; 0.95 [130]; 0.99 [45] | [19, 40, 45, 47, 50–52, 130, 133, 135, 136] | |
| S-demethylation (-CH2) | –15.7 | – | [132] | |
| –6 | Aromatization of saturated ring (-H6) | –47.0 | – | [152] |
| –2 | Alcohol oxidation to ketone/aldehyde (-H2) | –15.7 | 1.01 [83] | [83, 106] |
| Ring formation (-H2) | –15.7 | 1.20 [112] | [112] | |
| Oxidative defluorination (-F+OH) | +4.3 | – | [77, 147] | |
| –1 | Oxidative deamination to ketone/aldehyde (-NH3+O) | –31.6 | – | [142] |
| +1 | Oxidative deamination to alcohol (-NH+O) | –16.0 | – | [113] |
| Hydrolysis of amide to carboxyl (-NH+O) | –16.0 | – | [143] | |
| +2 | Ketone/aldehyde reduction to alcohol (+H2) | +15.7 | 0.72 [56]; 0.70 [40] | [33, 40, 56, 126] |
| Hydrogenation (+H2) | +15.7 | 1.13 [124] | [17, 124] | |
| Ring opening (+H2) | +15.7 | 0.59 [149] | [47, 149–151] | |
| +14 | Methyl/methylene oxidation to aldehyde/ketone (+O-H2) | –20.7 | 0.92, 1.02 [102]; 1.05 [45] | [45, 102] |
| Alcohol oxidation to carboxylic acid (+O-H2) | –20.7 | – | [106] | |
| Hydroxylation and cyclization (+O-H2) | –20.7 | – | [106] | |
| +16 | Hydroxylation (+O) | –5.1 | 0.38 [51]; 0.40 [131]; 0.46 [137]; 0.46, 0.50, 0.62 [124]; 0.51, 0.73, 0.82, 0.89, 0.96 [76]; 0.56 [40]; 0.58 [135]; 0.60, 0.62 [112]; 0.61 [45]; 0.69 [130]; 0.80 [52]; 0.82 [138]; 0.85 [102] | [23, 24, 40, 45, 47, 51, 52, 76, 83, 102, 108, 112, 124, 130, 131, 135–139] |
| Epoxidation (+O) | –5.1 | 0.56 [124]; 0.72 [140]; 0.89 [77] | [77, 124, 140, 141] | |
| N-oxidation (+O) | –5.1 | 0.93 [40]; 1.04 [45]; 1.09 [76] | [40, 45, 51, 76, 131, 136] | |
| S-oxidation of thioether to sulfoxide or sulfoxide to sulfone (+O) | –5.1 | 0.34 (S-SO) [141]; 0.82 (S-SO) [138]; 1.02 (SO-SO2) [143] | [138, 141, 143] | |
| Aldehyde oxidation to carboxyl (+O) | –5.1 | – | [126] | |
| Oxidation and ring formation (+O) | –5.1 | 0.46, 0.51 [137]; 0.53, 0.64 [80] | [80, 137] | |
| +18 | Ring opening by water addition (+H2O) | +10.6 | 1.10 [18] | [18, 19] |
| Hydrolysis of nitrile to amide (+H2O) | +10.6 | – | [45] | |
| +30 | Methyl oxidation to carboxylic acid (+O2-H2) | –25.8 | 0.24 [167]; 0.34 [40] | [40, 50, 167] |
| +32 | Dihydroxylation (+O2) | –10.2 | 0.49 [54]; 0.39 [124]; 0.80, 0.81 [160]; 0.84 [83]; 0.63, 0.67, 0.71, 0.79, 0.94 [76] | [54, 76, 83, 124, 160] |
| S-oxidation of thioether to sulfone (+O2) | –10.2 | 0.79 [138] | [138] | |
| +34 | Epoxidation and hydration (+H2O2) | +5.5 | 0.39 [124]; 0.47 [140]; 0.51, 0.68 [141] | [124, 140, 141] |
| +48 | Trihydroxylation (+O3) | –15.3 | – | [113] |
| S-oxidation of thiol to sulfonic acid (+O3) | –15.3 | – | [113] |
aThe parent drug has a relative retention shift (RRS) of 1.00.
bThe value of x corresponds to the length of the alkyl chain.
cRRS is related to another metabolite.