Parameter | Value | Methods/Reference |
---|---|---|
Molecular weight | 267.4 | Library a |
Log Po:w | 1.88 | Library |
pKa | 9.75 | Library |
B/P ratio | 1.15 | Library |
fu,p | 0.88 | Library |
Fa | 0.81 | Predicted b |
ka (h−1) | 0.58 | Predicted b |
Fg | 0.97 | Predicted by Qgut model |
Vss (l/kg) | 3.1 | Predicted c |
CL (l/h) | 55.8 | Predicted via IVIVEd |
CLr (l/h) | 4.27 | e |
Vmax (µl/min/mg) | Optimized f | |
O-demethylation | ||
Vmax,2D6 | 300 | |
Vmax,3A4 | 1164 | |
Alpha-OH | ||
Vmax,2D6 | 75.9 | |
Vmax,3A4 | 96 | |
Km,unbound (µM) | Library | |
O-demethylation | ||
Km,2D6 | 28.3 | |
Km,3A4 | 1162 | |
Alpha-OH | ||
Km,2D6 | 31 | |
Km,3A4 | 874 | |
fm and fe (2D6 EM) (%) | Predicted via IVIVE g | |
fm,2D6 | 84 | |
fm,3A | 7 | |
fe | 9 |
Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.
↵a Refers to Simcyp compound library (version 11.1).
↵b Predicted from human jejunum permeability (10−4 cm/s) (library data) in Simcyp (version 11.1).
↵c Not reported in the literature; predicted according to Rodgers and Rowland (2007).
↵d In vitro to in vivo extrapolation using in vitro Vmax and Km and average population values for liver weight and microsomal protein of 1618 g and 38.9 mg/g (liver), respectively. Reported CLIV in nonpregnant, CYP2D6 EMs and PMs is 72.5 ± 32.2 l/h (range 48.6–93.2 l/h) (number of studies = 3, number of subjects = 28, male only) and 30.1 ± 8.4 l/h (number of studies = 1, number of subjects = 3, male only) (University of Washington Drug Interaction Database, http://www.druginteractioninfo.org/). Reported CLIV in postpartum women is 39 ± 4.8 l/h (n = 5) (Hogstedt et al., 1985).
↵e Reported mean value in nonpregnant, CYP2D6 EMs and PMs is 4.27 l/h (range 3.24–6.0 l/h) (number of studies = 6, number of subjects = 67) (University of Washington Drug Interaction Database, http://www.druginteractioninfo.org/).
↵f IVIVE (in vitro-in vivo extrapolation) approach using in vitro Vmax determined in human liver microsomes (provided in library) significantly underpredicted CLIV and CLORAL by a factor of 2.2 and 2.3 in nonpregnant, CYP2D6 EMs. This underprediction was also evident in nonpregnant, CYP2D6 PMs (by a factor of 3.2 and 1.4, respectively). To improve IVIVE prediction of CL, in vivo Vmax for CYP2D6 and 3A4 was optimized by multiplying in vitro Vmax by a factor of 2.
↵g Literature fm,2D6 = 69.5–82.8% (Brown et al., 2005; Ito et al., 2005).