RT Journal Article
SR Electronic
T1 A Convenient In Vitro Screening Method for Predicting In Vivo Drug Metabolic Clearance Using Isolated Hepatocytes Suspended in Serum
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1518
OP 1523
VO 28
IS 12
A1 Shibata, Yoshihiro
A1 Takahashi, Hiroyuki
A1 Ishii, Yasuyuki
YR 2000
UL http://dmd.aspetjournals.org/content/28/12/1518.abstract
AB A novel and convenient in vitro method for predicting in vivo metabolic clearance in the liver (CLH) was developed. The CLH of a drug is usually predicted by using both the unbound fraction in serum and the intrinsic hepatic clearance of the unbound fraction, but this procedure is labor-intensive. We simplified the method by directly measuring intrinsic hepatic clearance using isolated rat hepatocytes suspended in rat serum and called this “the serum incubation method”. Sixteen commercially available compounds reported to be mainly excreted by liver metabolism were evaluated using our method. The remaining ratio of the unchanged drug after incubation was measured to calculate the rate of metabolism, and then CLH was predicted based on the dispersion model. The predicted CLH values of the drugs estimated by the serum incubation method were in good agreement with their in vivo plasma clearance values. In addition, the intrinsic hepatic clearance values obtained by the serum incubation method were comparable with those obtained by conventional methods. Furthermore, oral bioavailability values were equal to or lower than hepatic availability values predicted from the serum incubation method. These results indicate that compounds showing poor oral bioavailability can be excluded before in vivo pharmacokinetic study by using this method. In conclusion, the serum incubation method is a convenient and useful tool at the early stage of drug discovery. The American Society for Pharmacology and Experimental Therapeutics