TABLE 1.
Intrinsic clearance by pooled HLM and relative rates of glucuronidation by HLM(-), UGT2B10, and UGT1A4 for known UGT2B10, newly identified UGT2B10 substrates, and control compounds
Relative activity factors for UGT1A4 (trifluoperazine) = 0.31, for UGT2B10 (RO5263397 and dexmedetomidine) = 4.3, and for UGT2B10 (cyclizine, chlorcyclizine, nicotine, cotinine) = 11–15.9.
| Category | Drug | Conc. | Pooled HLM Clint | Percentage of Metabolite Appearance Ratea | Ref.b | |||
|---|---|---|---|---|---|---|---|---|
| µM | µl/min per milligram | Pooled HLM | HLM(-) | Rec. UGT2B10 | Rec. UGT1A4 | |||
| Known UGT2B10 substrates | Amitriptyline | 5 | 2.5 ± 0.6 | 100 ± 2 | 14 ± 0 | 17 ± 1 | 28 ± 1 | Zhou et al., 2010 |
| RO5263397 | 1 | 35 ± 3 | 100 ± 6 | 3.2 ± 0.2 | 23 ± 2 | 5.1 ± 0.3 | Fowler et al., 2015 | |
| Nicotine | 100 | <1.1 | 100 ± 9 | 2.6 ± 0.1 | 8.3 ± 0.7 | 0.60 ± 0.05 | Chen et al., 2007 | |
| Cotinine | 100 | <1.1 | 100 ± 4 | 1.6 ± 0.2 | 8.3 ± 0.8 | 1.5 ± 0.3 | Chen et al., 2007 | |
| Dexmedetomidinec | 1 | 17 ± 1 | 100 ± 3 | 3.3 ± 0.2 | 23 ± 1 | 10 ± 1 | Kaivosaari et al., 2008 | |
| Desloratadine | 10 | <1.1 | 100 ± 13 | <2.3 | <0.5 | <0.5 | Kazmi et al., 2015 | |
| Cyclizine | 10 | 16 ± 2 | 100 ± 0 | 1.8 ± 0.1 | 6.3 ± 0.2 | 1.7 ± 0.2 | Lu et al., 2018 | |
| Chlorcyclizine | 10 | 17 ± 5 | 100 ± 1 | 3.1 ± 0.1 | 9.1 ± 0.3 | 7.1 ± 0.6 | Lu et al., 2018 | |
| New selective UGT2B10 substrates | Cyclobenzaprine | 10 | 2.1 ± 0.7 | 100 ± 7 | 8.5 ± 1.4 | 18 ± 4 | 28 ± 9 | Lu et al., 2017 |
| Dothiepin | 10 | 3.7 ± 0.6 | 100 ± 5 | 8.4 ± 0.5 | 16 ± 0 | 35 ± 3 | Lu et al., 2017 | |
| Cidoxepin | 1 | 6.0 ± 0.3 | 100 ± 6 | 1.8 ± 0.7 | 2.1 ± 0.3 | 1.8 ± 1.3 | Lu et al., 2017 | |
| Cyproheptadine | 1 | 23 ± 3 | 100 ± 7 | 3.3 ± 0.1 | 6.0 ± 0.7 | 1.8 ± 0.2 | Lu et al., 2017 | |
| Azatadine | 1 | 14 ± 1 | 100 ± 1 | 1.5 ± 0.2 | 5.3 ± 0.6 | <0.5 | Villani, 1967 | |
| Bifonazole | 1 | 11 ± 1 | 100 ± 12 | 12 ± 1 | 13 ± 4 | 193 ± 7 | Bourcier et al., 2010 | |
| Asenapine | 1 | 27 ± 2 | 100 ± 8 | 4.6 ± 0.3 | 20 ± 2 | 60 ± 5 | Lu et al., 2017 | |
| Other N-gluc. Substrates | Trifluoperazine | 5 | 4.0 ± 0.7 | 100 ± 4 | 59 ± 1 | <0.5 | 325 ± 47 | Lu et al., 2017 |
| Rupatadine | 1 | <1.1 | 100 ± 7 | 52 ± 4 | <0.5 | 1640 ± 622 | Solans et al., 2007 | |
| Tioconazole | 1 | 18 ± 1 | 100 ± 4 | 31 ± 1 | 5.0 ± 0.2 | 77 ± 14 | Bourcier et al., 2010 | |
<2.3, 1.1, and 0.5 indicate Clint of glucuronide formation below the limit of quantification. Relative activity factors for UGT1A4 (trifluoperazine) = 0.31, for UGT2B10 (RO5263397 and dexmedetomidine) = 4.3, and for UGT2B10 (cyclizine, chlorcyclizine, nicotine, cotinine) = 11–15.9.
Reference for substrate identification as UGT substrate.
The contribution of both dexmedetomidine glucuronides was used in the metabolite formation rate calculation.