Jc. Bloomer et al., IN-VITRO IDENTIFICATION OF THE P450 ENZYMES RESPONSIBLE FOR THE METABOLISM OF ROPINIROLE, Drug metabolism and disposition, 25(7), 1997, pp. 840-844
The in vitro metabolism of ropinirole was investigated with the aim of
identifying the cytochrome P450 enzymes responsible for its biotransf
ormation. The pathways of metabolism after incubation of ropinirole wi
th human liver microsomes were N-despropylation and hydroxylation. Enz
yme kinetics demonstrated the involvement of at least two enzymes cont
ributing to each pathway. A high affinity component with a K-M of 5-87
mu M and a low affinity component with a K-M of approximately two ord
ers of magnitude grater were evident. The high affinity component coul
d be abolished by pre-incubation of the microsomes with furafylline. A
dditionally, incubation of ropinirole with microsomes derived from CYP
1A2 transfected cells readily produced the N-despropyl and hydroxy met
abolites. Some inhibition of ropinirole metabolism was also observed w
ith ketoconazole, indicating a minor contribution by CYP3A. Multivaria
te correlation data were consistent with the involvement of the cytoch
rome P450 enzymes 1A2 and 3A in the metabolism of ropinirole. Thus, it
could be concluded that the major P450 enzyme responsible for ropinir
ole metabolism at lower (clinically relevant) concentrations is CYP1A2
with a contribution from CYP3A, particularly at higher concentrations
.