Intrinsic clearances regarding the hepatic clearance of statins in humans
All the intrinsic clearances are scaled up to the in vivo clearance values per unit liver weight using the following physiological scaling factors: 24.1 g liver/kg, 1.2 × 108 cells/g liver, and 48.8 mg microsomal protein/g liver. Data represent the mean ± S.E. (n = 3).
| Uptake Clearance | Metabolic Clearance | Overall Intrinsic Clearance | |||
|---|---|---|---|---|---|
| PSinf,vitroa | Scaling Factorb | PSinf,vivo,predictedc | CLmet,int,vitrod | CLint,all,vivo | |
| ml/min/g liver | ml/min/g liver | ml/min/g liver | |||
| Pravastatin | 0.575 ± 0.090 | 2.5 ± 0.1 | 1.44 ± 0.24 | N.D.e | 0.84–1.2f |
| Pitavastatin | 18.5 ± 3.8 | 1.7 ± 0.3 | 30.6 ± 8.9 | 0.248 ± 0.081 | 14–35g |
| Atorvastatin | 6.99 ± 0.55 | 1.8 ± 0.3 | 12.7 ± 2.3 | 2.98 ± 0.06 | 11–19f |
| Fluvastatin | 14.5 ± 0.8 | 4.3 ± 0.5 | 62.9 ± 8.4 | 5.57 ± 0.28 | 123–185h |
↵a Determined using human hepatocytes at 0.1 μM.
↵b Obtained from rats studies. These values were calculated by dividing PSinf,MID by PSinf,vitro in rats (Table 3).
↵c Calculated by multiplying PSinf,vitro determined using human hepatocytes by the corresponding scaling factor obtained in rats.
↵d Determined using human liver microsomes.
↵e No metabolism was detected in human S9 (Watanabe et al., 2009).
↵f Calculated from the plasma concentration and urinary excretion data after intravenous administration in the clinical studies (Singhvi et al., 1990; FDA-approved package).
↵g Calculated from the plasma concentration and urinary excretion data after oral administration in the clinical studies (Ando et al., 2005) and the fraction absorbed in rats (0.83) (Kimata et al., 1998). The details of this estimation are described in the text.
h Calculated from bioavailability and fraction absorbed in the clinical studies.