Interaction of enoxacin with theophylline in rats

Enoxacin (ENX) has been reported to raise significantly plasma levels of theophylline (TP) in humans. In order to elucidate a mechanism of this interaction, in vivo and in vitro studies were carried out in rats. Concomitant dosing of ENX with TP significantly elongated plasma elimination half-life of TP, which led to a marked increase in the maximum plasma TP level after repeated administrations of both drugs. In rats treated with ENX, urinary excretion of unchanged TP increased and that of TP metabolites comparably decreased. The pharmacokinetic analysis showed that ENX did not change renal clearance of TP and these observed effects of ENX were attributed to reduced metabolic clearance of TP. In the in vitro studies by using liver microsomes, ENX reduced the magnitude of the type II difference spectral interaction of TP with cytochrome P-448 (P-448) and the formation of TP metabolites catalyzed by P-448. These results strongly suggest that the inhibition of the TP binding to the ferric iron of P-448 leads to that of the TP metabolism. The most essential site of ENX to inhibit the TP metabolism was found to be the 4'-nitrogen atom in the 7-piperazinyl group, and the stereochemical structure of ENX was suggested to be responsible for this inhibition.