Aliphatic-type quaternary ammonium–linked glucuronide metabolites of drugs identified in human urine
| Drug | Qualitative Identification | Quantitative Analysis | References | ||||
|---|---|---|---|---|---|---|---|
| Reference Standard1-a | 1H NMR1-b δ | Soft Ionization MS1-c | Other1-d | Technique1-e | Mean % Dose Excreted in Urine as N+-Glucuronide (N)1-f | ||
| H1 Antihistamines and related drugs | |||||||
| Chlorpheniramine | OS | 4.71 | FAB | HPLC-UV | 1.1 (2) | Luo et al., 1991a,1992b | |
| Cyclizine | OS | 4.83 | FAB | HPLC-UV | 14.3 (2) | Luo et al., 1991a, 1992b | |
| Cyproheptadine | NA | NG | ND | EI MS, IND, IR | IND | 6.6 ± 1 (3); 12.4 ± 4 (6); 24 ± 9 (5) | Porter et al., 1975; Kennedy et al., 1977;Beckett and Ali, 1978; Fischer et al., 1980 |
| Diphenhydramine | OS | 4.58 | FAB | HPLC-UV | 4.0 (2) | Luo et al., 1991a, 1992b | |
| Doxylamine | OS | 4.77 | FAB | HPLC-UV | 0.9 (2) | Luo et al., 1991a, 1992b | |
| Homochlorcyclizine | NA | ND | ND | IND | IND | 3.9 ± 0.5 (3) | Nishikata et al., 1992, 1993 |
| Ketotifen | NA | ND | ND | IND | IND | 23.8 ± 3.5 (6) | Guerret et al., 1981; Bigot et al., 1987 |
| Pheniramine | OS | 4.69 | FAB | HPLC-UV | 1.2 (2) | Luo et al., 1991a, 1992b | |
| Promethazine | OS | 4.86 | FAB | HPLC-UV | 0.2 (2) | Luo et al., 1991a, 1992b | |
| Pyrilamine | OS | 4.73 | FAB | IND | HPLC-UV | 0.6 (2) | Luo et al., 1991a, 1992b; Chung et al.,1994 |
| Tripelennamine | OS | 4.73 | FAB | EI MS, IND, IR | HPLC-UV | 6.6 (2) | Chaudhuri et al., 1976; Luoet al., 1991a, 1992b |
| Tricyclic antidepressants and related drugs | |||||||
| Amitriptyline | BS | 4.51 | FAB | IND, UV | HPLC-UV | 7.8 ± 5.2 (5); 8.2 ± 3.2 (15); 9.8 ± 10 (3) | Lehman et al., 1983;Dahl-Puustinen and Bertilsson, 1987; Dahl-Puustinen et al.,1989; Breyer-Pfaff et al., 1990; Luo et al.,1992b |
| E- orZ-10-Hydroxyamitriptyline1-g | NA | 4.40–4.58 (two d in this range) | FAB | IND, UV | HPLC-UV | 3.2 ± 1.1 (3) | Breyer-Pfaff et al., 1990 |
| trans-10,11-Dihydroxyamitriptyline1-g | NA | 4.47, 4.52 (two d) | FAB | IND, UV | ND | Breyer-Pfaff et al., 1990 | |
| Clomipramine | OS | 4.51 | FAB | HPLC-UV | 0.3 ± 0.3 (3); 0.2 ± 0.1 (3) | Luo et al., 1995 | |
| Cyclobenzaprine | NA | ND | ND | IND | IND | 18.6 ± 0.6 (3)1-h | Hucker et al., 1978a, 1978b |
| Dothiepin | NA | ND | ND | IND | IND | 10.6 ± 1.9 (5) | Kawahara et al., 1986 |
| Doxepin | OS | 4.44 | FAB | HPLC-UV | 22.8 (2) | Luoet al., 1991b, 1992b | |
| Imipramine | BS, OS | 4.34 | FAB | HPLC-UV | 0.8 ± 0.5 (3) | Lehmanet al., 1983; Luo et al., 1992b, 1995 | |
| Mianserin | NA | 4.7 | FAB | RA | 16 (3) | Delbressine et al., 1992 | |
| Trazodone | OS | 4.61 | FAB | HPLC-UV | 0.2 (1); 0.1 ± 0.02 (3) | Luo et al., 1995 | |
| Trimipramine | OS | 4.50, 4.56 (two d) | FAB | HPLC-UV | 0.3 (2); 0.1 ± 0.04 (3) | Luoet al., 1995 | |
| Antipsychotic agents | |||||||
| Chlorpromazine | BS, OS | 4.58 | FAB | HPLC-UV | <0.1% (5) | Chaudhary et al., 1988; Luo et al., 1992b, 1995 | |
| Clozapine | OS | 4.98 | API, FAB | HPLC-UV | 3.1 ± 4.0 (3) | Luo et al.,1992b, 1994, 1995 | |
| Loxapine | OS | 5.00 | FAB | HPLC-UV | 1.6 ± 0.7 (3) | Luo et al., 1992b, 1995 | |
NA, not available; ND, not determined; NG, data not given.
↵1-a BS, prepared by biochemical synthesis; OS, prepared by organic synthesis.
↵1-b Chemical shift data (δ units) given for anomeric proton; one (d) except where indicated.
↵1-c Molecular cation assigned using API (atmospheric pressure ionization–type technique) or FAB (fast atom bombardment).
↵1-d EI MS, Electron impact mass spectrometry; IND, indirect identification by analysis of the aglycone released by β-glucuronidase and/or base treatment; IR, infrared spectroscopy; UV, ultraviolet spectroscopy.
↵1-e IND, indirect quantification by analysis of the aglycone released by β-glucuronidase or base treatment; RA, radiometric assay.
↵1-f Data expressed as mean + SD (N) and obtained after oral administration.
↵1-g After administration of amitriptyline.
↵1-h Mean percentage of urinary metabolites.