Prediction of CLint in human liver microsomes from enzyme kinetic parameters from cDNA-expressed enzymes for R-omeprazole
| Enzyme | CYP2C19 | CYP2C9 | CYP3A4 | CYP2A6 | CYP2D6 | Total CLint |
|---|---|---|---|---|---|---|
| μl/min · mg | ||||||
| Sulfone | — | — | 2.02 | — | — | 2.02 |
| 5-O-desmethyl | 1.24 | — | — | — | 0.03 | 1.27 |
| Hydroxy | 29.8 | — | 2.42 | — | 0.04 | 32.3 |
| ΣCLint | 31.0 | — | 4.44 | — | 0.07 | 35.6 |
| % total CLint | 87 | — | 12.5 | 0.20 |
The percentage of each P450 in human liver microsomes was estimated to be: CYP2C19 2% (Yamazaki et al., 1997), CYP2C9 18%, CYP3A4 28%, CYP2A6 4%, and CYP2D6 1.5% (Shimada et al., 1994). Total CYP content in a typical preparation is 0.46 nmol/mg of microsomal protein. The nanomole per milligram of protein content of each CYP enzyme was therefore estimated to be: CYP2C19: 0.0092, CYP2C9: 0.083, CYP3A4: 0.129, CYP2A6: 0.018, and CYP2D6: 0.0069. These values were used to predict CLint in human liver microsomes from the CLint values in Tables 4 and 5 obtained by using expressed enzymes.
—, indicates that no metabolite was detected.