PT  - JOURNAL ARTICLE
AU  - Shibata, Yoshihiro
AU  - Takahashi, Hiroyuki
AU  - Ishii, Yasuyuki
TI  - A Convenient In Vitro Screening Method for Predicting In Vivo Drug Metabolic Clearance Using Isolated Hepatocytes Suspended in Serum
DP  - 2000 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1518--1523
VI  - 28
IP  - 12
4099  - http://dmd.aspetjournals.org/content/28/12/1518.short
4100  - http://dmd.aspetjournals.org/content/28/12/1518.full
SO  - Drug Metab Dispos2000 Dec 01; 28
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