Kinetic parameters of paroxetine biotransformation by CP450 isoforms and HLMs
Kinetic data for the P450 isoforms and PM CYP2D6 sdHLMs(1) using paroxetine-catechol formation are estimated by eq. 4 or eq. 6. Kinetic data for pHLMs are estimated by eq. 5. pHLMs(1) and pHLMs(2) refer to the two different terms in eq. 5. Kinetic data for paroxetine depletion were estimated by eq. 2. S.E. was estimated by nonlinear regression. Units of measure are as follows: Km and Ks, micromolar concentrations; Vmax (P450), picomoles per minute per picomole of P450, Vmax (HLMs), picomoles per minute per milligram of protein; and Clint, nanoliter per minute per picomoles of P450.
| CYP1A2 | CYP2C19 | CYP2D6 | CYP3A4 | CYP3A5 | pHLMs(1) | pHLMs(2) | PM CYP2D6 sdHLMs(1) | |
|---|---|---|---|---|---|---|---|---|
| Paroxetine-catechol formation | ||||||||
| Km (best fit value ± S.E.) | 8.8 ± 1.9 | 26.0 ± 4.9 | 0.028 ± 0.002 | 13.3 ± 1.1 | 108 ± 10 | 0.24 ± 0.18 | 8 ± 6 | 31 ± 3 |
| Vmax (best fit value ± S.E.) | 0.63 ± 0.06 | 2.43 ± 0.29 | 9.7 ± 0.1 | 5.32 ± 0.22 | 1.6 ± 0.1 | 65 ± 23 | 81 ± 21 | 300 ± 8 |
| Ks (best fit value ± S.E.) | 141 ± 38 | 131 ± 34 | 298 ± 48 | |||||
| Assay protein concentration (mg/ml) | 0.45 | 0.10 | 0.012 | 0.24 | 0.45 | 0.20 | 0.20 | 0.20 |
| Km corrected by fua | 2.0 | 14.8 | 0.026 | 4.7 | 25 | 0.096 | 3.2 | 12.4 |
| Ks corrected by fua | 32 | 75 | 106 | |||||
| Clint (Vmax/Km) (free concentration) | 320 | 164 | 373,000 | 1130 | 64 | — | — | — |
| Paroxetine depletion | ||||||||
| Km (best fit value ± S.E.) | — | 0.36 ± 0.13 | 0.057 ± 0.033 | — | — | — | — | — |
| Vmax (best fit value ± S.E.) | — | 0.23 ± 0.06 | 3.29 ± 1.09 | — | — | — | — | — |
| Assay protein concentration (mg/ml) | 0.10 | 0.0178b | ||||||
| Km corrected by fua | 0.20 | 0.050 | ||||||
| Clint(Vmax/Km) (free concentration) | 1150 | 65,800 |