Table 2.
Kinetic parameters for competing terbinafine oxidation pathways in recombinant P450s.a
| P450 isozyme | Substrate | Steady-state kinetic constants for individual metabolites | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Vmaxb | Km or S50 (μM) | Hill slope (n)c | Vmax/Km | Vmaxb | Km or S50 (μM) | Hill slope (n)c | Vmax/Km | |||
| CYP1A2 | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| 76 ± 2.5 | 45 ± 5.7 | - | 1.7 | 1200 ± 31 | 130 ± 87 | 1.5 ± 0.20 | - | |||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafine dihydrodiol | ||||||||
| undetected | undetected | |||||||||
| CYP2B6 | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| 76 ± 2.598 ± 17 | 300 ± 100 | - | 0.32 | 14 ± 1.5 | 24 ± 10 | - | 1.7 | 0.5 | ||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafinedihydrodiol | ||||||||
| linear | - | - | 0.0081d | 0.59 ± 0.13 | 280 ± 130 | - | 0.0026 | |||
| CYP2C8 | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| undetected | undetected | |||||||||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafine dihydrodiol | ||||||||
| 0.61 ± 0.04 | 75 ± 18 | - | 0.0081 | undetected | ||||||
| CYP2C9 | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| undetected | 14 ± 0.6 | 72 ± 92 | 1.8 ± 0.49 | - | ||||||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafine dihydrodiol | ||||||||
| undetected | 2.0 ± 0.07 | 15 ± 3 | - | 0.13 | ||||||
| CYP2C19e | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| 210 ± 7 | 44 ± 2.9 | 1.40 ± 0.11 | 110 ± 17 | 110 ± 63 | 0.58 ± 0.08 | |||||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafine dihydrodiol | ||||||||
| 9.3 ± 0.33 | 52 ± 7.4 | - | 0.18 | 26 ± 1 | 68 ± 9.5 | - | ||||
| CYP2D6 | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| 57.0 ± 2.1 | 16 ± 3.2 | - | 3.6 | 30 ± 1.4 | 25 ± 4.1 | - | 3.8 | |||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafine dihydrodiol | ||||||||
| undetected | undetected | |||||||||
| CYP3A4e | terbinafine | hydroxyterbinafine | terbinafine dihydrodiol | |||||||
| 570 ± 20 | 25 ± 2.3 | 1.30 ± 0.16 | 150 ± 3.3 | 17.6 ± 1.3 | 2.0 ± 0.32 | |||||
| desmethyl-terbinafine | desmethyl hydroxyterbinafine | desmethyl-terbinafine dihydrodiol | ||||||||
| 0.53 ± 0.04 | 82 ± 20 | - | 0.0065 | 2.3 ± 0.17 | 98 ± 19 | - | 0.023 | |||
Data fit to the Michaelis-Menten equation or the Hill equation based on extra sum-of-squares F test (P < 0.05) using GraphPad Prism 7.0. Values shown with standard deviation from mean.
Due to absence of authentic standards, rates reflect normalized MS peak area for metabolite as a function of time, i.e. μV*sec/min/nmol. Final values were scaled x106.
Not shown in table: n=1 for Michaelis-Menten equation.
Efficiency expressed as slope of formation rate over substrate concentration due to lack of observed saturation.
Data taken from Davis et al. (2019). Normalized peak areas (μV*sec) reported from that study were converted to rates (μV*sec/min/nmol) by dividing by protein concentration (100 nM) and reaction time (30 min). This scaled conversion of the values does not change the shape of the plotted curve.