BACKGROUND: Although it is important to maintain an appropriate blood concentration of FK506 after liver transplantation, significant interindividual variability in the actual FK506 dosage has been observed, presumably due to the wide variability of cytochrome P450 3A4 activity in liver microsomes. METHODS: A study was conducted in patients undergoing living-related liver transplantation and their donors to investigate the relationship between the in vitro FK506 demethylation activity in graft liver microsomes and the in vivo blood clearance of FK506. Liver biopsy tissue was obtained from 17 living donors to measure the in vitro formation rate of 13-demethyl derivative (M-I: the major metabolite of FK506). Erythromycin N-demethylation activity in vitro was also assessed in 11 cases. The FK506 blood clearance (CLss) was calculated from its constant infusion rate and steady-state blood concentration on day 4 after transplantation in 17 recipients. RESULTS: The FK506 infusion 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 formation rate showed a wide variability, ranging from 0.098 to 0.571 nmol/min/mg protein. A significant correlation was observed between the in vitro estimated total metabolic ability of the graft for FK506 (M-I formation 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=0.891, P<0.01). CONCLUSIONS: The in vivo FK506 clearance can mainly reflect in vitro FK506 demethylation activity.
BACKGROUND: Although it is important to maintain an appropriate blood concentration of FK506 after liver transplantation, significant interindividual variability in the actual FK506 dosage has been observed, presumably due to the wide variability of cytochrome P450 3A4 activity in liver microsomes. METHODS: A study was conducted in patients undergoing living-related liver transplantation and their donors to investigate the relationship between the in vitro FK506 demethylation activity in graft liver microsomes and the in vivo blood clearance of FK506. Liver biopsy tissue was obtained from 17 living donors to measure the in vitro formation rate of 13-demethyl derivative (M-I: the major metabolite of FK506). Erythromycin N-demethylation activity in vitro was also assessed in 11 cases. The FK506 blood clearance (CLss) was calculated from its constant infusion rate and steady-state blood concentration on day 4 after transplantation in 17 recipients. RESULTS: The FK506 infusion 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 formation rate showed a wide variability, ranging from 0.098 to 0.571 nmol/min/mg protein. A significant correlation was observed between the in vitro estimated total metabolic ability of the graft for FK506 (M-I formation 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=0.891, P<0.01). CONCLUSIONS: The in vivo FK506 clearance can mainly reflect in vitro FK506 demethylation activity.