RELATIONSHIP BETWEEN IN-VIVO FK506 CLEARANCE AND IN-VITRO 13-DEMETHYLATION ACTIVITY IN LIVING-RELATED LIVER-TRANSPLANTATION

Background. Although it is important to maintain an appropriate blood concentration of FK506 after liver transplantation, significant interi ndividual variability in the actual FK506 dosage has been observed, pr esumably due to the wide variability of cytochrome P450 3A4 activity i n liver microsomes. Methods. A study was conducted in patients undergo ing living-related liver transplantation and their donors to investiga te the relationship between the in vitro FK506 demethylation activity in graft liver microsomes and the in vivo blood clearance of FK506. Li ver biopsy tissue was obtained from 17 living donors to measure the in vitro formation rate of 13-demethyl derivative (M-I: the major metabo lite of FK506). Erythromycin N-demethylation activity in vitro was als o assessed in 11 cases. The FK506 blood clearance (CLss) was calculate d from its constant infusion rate and steady-state blood concentration on day 4 after transplantation in 17 recipients. Results. The FK506 i nfusion rate varied 4.6-fold from 8.3 to 38.4 ng/min/kg. The mean CLss of FK506 was 22.1 +/- 10.8 ml/min (10.1-45.2 ml/min). The M-I formati on rate showed a wide variability, ranging from 0.098 to 0.571 nmol/mi n/mg protein. A significant correlation was observed between the in vi tro estimated total metabolic ability of the graft for FK506 (M-I form ation rate x graft weight) and the in vivo CLss of FK506 (r=0.770, P<0 .001), Erythromycin N-demethylation (0.066-0.443 nmol/min/mg protein) showed a strong correlation with the M-I formation rate (r=8.891, P<0. 01). Conclusions. The in vivo FK506 clearance can mainly reflect in vi tro FK506 demethylation activity.