The constants and types of inhibition of gemfibrozil for human P450 isoform activities and the predicted in vivo inhibition of the metabolism of coadministered CYP2C9, CYP2C19, and CYP1A2 substrates by gemfibrozil from in vitro data
| P450 [Ki1-a(μM), type of inhibition] | Cmax | Cmean | Cmax,u | Cmean,u | |
|---|---|---|---|---|---|
| [I] (μM) | 151 ± 39 | 39 ± 22 | 8 ± 2 | 1.9 ± 1.1 | |
| (116 − 253) | (18 − 94) | (6 − 13) | (0.9 − 4.7) | ||
| [I]/([I] + K i) (%) | CYP2C9 | 96 ± 1 | 85 ± 5 | 56 ± 5 | 24 ± 9 |
| (5.8, competitive) | (95 − 98) | (76 − 94) | (52 − 68) | (14 − 45) | |
| CYP2C19 | 86 ± 2 | 58 ± 11 | 24 ± 4 | 7 ± 4 | |
| [24, mixed (α1-b = 7.3)] | (83 − 91) | (43 − 80) | (21 − 34) | (4 − 16) | |
| CYP1A2 | 64 ± 5 | 30 ± 10 | 8 ± 2 | 2 ± 1 | |
| [82, mixed (α1-b = 7.3)] | (59 − 75) | (18 − 53) | (7 − 13) | (1 − 5) |
Data are expressed as mean ± S.D. (range). The plasma concentrations of gemfibrozil were taken from Backman et al., (2000); gemfibrozil (600 mg) was administered twice daily for 3 days to 10 healthy volunteers. Cmax, peak total plasma concentration of gemfibrozil; Cmean, mean total plasma concentration of gemfibrozil during a 12-hour-dosing interval; Cmax,u, unbound peak gemfibrozil concentration in plasma estimated by a plasma protein binding of 95% (Dollery, 1999); Cmean,u, unbound mean plasma concentration of gemfibrozil during a 12-hour-dosing interval.
↵1-a Values (mean of duplicate determinations) are derived from nonlinear regression analysis based on coincubation of the respective CYP specific substrates with various concentrations of gemfibrozil without preincubation at 37° C (seeExperimental Procedures for details). Ki values were not calculated for CYP2A6, CYP2D6, CYP2E1, and CYP3A4, because the IC50 values were >250 μM.
↵1-b α is the factor by whichKm changes when inhibitor occupies the enzyme site.