IVIVC of intrinsic clearance using the dog hepatocyte relay method

CompoundsIn Vivo Dog Intrinsic ClearanceaIn Vitro Intrinsic Clearance from Dog Hepatocyte Relay Method ± S.D.Fold Difference In Vivo/Relay Method
Ranitidine7.7 (Bayliss and Cross, 2000)7.4 ± 0.61.0
Tolbutamide11b (Kimura et al., 1999)9.0 ± 3.91.2
Antipyrine14 (Balani et al., 2002)14 ± 1.41.0
Naproxen22c (Suh et al., 1997)20 ± 3.01.1
(±)-Ketoprofen48 – 114d (Granero and Amidon, 2008; Neirinckx et al., 2011)24 ± 1.22.0–4.7e
  • a Fu and Rb values were from the literature (Berry et al., 2011) or in-house data.

  • b The equation CLiv = oral dose (DosePO)/oral area under the curve (AUCPO) × F was used to derive i.v. clearance.

  • c PK profile (Suh et al., 1997) was digitized and i.v. clearance value was calculated using WinNonlin (Centara, Sunnyvale, CA).

  • d Two i.v. studies were reported in the literature (Granero and Amidon, 2008; Neirinckx et al., 2011). One used racemic ketoprofen in mongrel dogs with three different doses (Granero and Amidon, 2008), and the other was a beagle dog study with individual enantiomers (Neirinckx et al., 2011). The clearance values of the individual enantiomers were converted to that of the racemate using dose (sum of the two enantiomers) divided by AUC (sum of the two enantiomers) (Neirinckx et al., 2011). It gave a similar clearance value (CLint 113 ml/min/kg) as that in the racemate study with mongrel dog (CLint 48–114 ml/min/kg). Therefore, data from both reports were included for IVIVC determination.

  • e The in vitro–in vivo differences may be due to extrahepatic contribution of UGT [e.g., kidney metabolism (Granero and Amidon, 2008)].