TABLE 3

Pharmacokinetic parameters of PNU-96391 in rat, dog, monkey, and human hepatocytes PNU-96391 at 0.5 μM was incubated in hepatocytes (ca. 1 × 106 viable cells/ml) in Krebs-Henseleit buffer containing 10 mM HEPES at 37°C up to 120 min. PNU-96391 concentrations were determined by LC/MS-MS after protein precipitation, and pharmacokinetic parameters were calculated using scaling factors to in vivo basis followed by dispersion model analysis (mean ± S.D.; n = 4 in rats and monkeys, n = 8 in dogs and humans).


Species

t1/2,z

CLint

CLhep
h l/h/106 cells l/h/kg l/h/kg
Rat 0.34 ± 0.03 0.93 ± 0.17 4.5 ± 0.8 2.2 ± 0.2
Dog 1.2 ± 0.8 0.57 ± 0.27 2.2 ± 1.0 0.94 ± 0.31
Monkey 0.48 ± 0.01 0.54 ± 0.13 2.1 ± 0.3 1.2 ± 0.1
Human
4.2 ± 2.3
0.18 ± 0.09
0.56 ± 0.26
0.32 ± 0.13