抄録
Inhibitory effect of E4080 on the cytochrome P450 was studied using laboratory animals in vitro and in vivo.
In vitro study E4080 has a high affinity for P450 heme in rat, dog, monkey and human liver microsomes. In rat microsomes, E4080 inhibited testosterone 6β and 16β-hydroxylase which are involved in CYP2B and CYP3A. Using human microsomes, E4080 inhibited metabolism of 7-benzyloxyresolfin, tolbutamide, bufuralol and testosterone. These results suggest that E4080 inhibits CYP 2B6, 2C9, 2D6 and 3A4 in human liver microsomes.
In vivo study E4080 prolonged antipyrine half-life and decreased antipyrine clearance in rats, dogs and monkeys at the doses of 10mg/kg which exert pharmacological effect postulated from the minimal effective plasma concentrations(1-2 μg/ml ). The results may be suggested that E4080 interacts with antipyrine metabolism which is thought to be carried out by CYP 1A, 2C and 3A.
In the clinical trial E4080 (100mg/man) decreased the excretion of urinary 6β-hydroxycortisol which is a marker of human hepatic cytochrome P4503A induction and inhibition.
In conclusion, it is suspected that E4080 inhibits CYP3A not only in animals, but also in human and should be noticed drug-drug interaction in clinical use.
