Abstract
In order to elucidate the mechanism of interaction of enoxacin (ENX) with theophylline (TP), we investigated the effect of ENX on the plasma and urine levels of TP in rats. The results were as follows.
1. Three concomitant oral doses of ENX at 50, 100 and 300 mg/kg with TP (15 mg/kg once orally) prolonged the plasma elimination half-life of TP from the control value of 3. 8 h to 4. 7, 6. 0 and 7. 4 h. However, treatment with ENX did not affect the maximum plasma level of TP.
2. After 3-day pretreatment with ENX (300 mg/kg three times daily), the TP alf-life on the fourth day (3.7 h) was similar to the control value (3.8 h) described above, showing only a shortlasting effect of ENX on the TP half-life.
3. In the 3-day repeated concomitant dose test of ENX (300 mg/kg three times daily) with TP (15 mg/kg twice daily), the maximum plasma TP level on the third day (in steady state) rose 1.4-fold over that on the first day.
4. In rats treated with ENX (300 mg/kg three times), 24-h urinary excretion of unchanged TP after a single TP dose (15 mg/kg) increased from the control level of 25.6%(of the dose) to 45.0%, while those of 1-methyluric acid and 1, 3-dimethyluric acid (TP metabolites) comparably decreased from 16.7% and 27.4% to 8.2% and 13.5%, respectively. Pharmacokinetic analysis demonstrated that treatment with ENX remarkably decreased total body clearance of TP from the control value of 103 ml/kg/h to 62 ml/kg/h and metabolic clearance from 78 ml/kg/h to 35 ml/kg/h, but did not change renal clearance (27 ml/kg/h) from the control value (25 ml/kg/h).
5. Consequently, an increase in the plasma TP level after repeated doses of ENX and TP is probably attributable to prolongation of the TP half-life based on the reduced metabolic clearance of TP by ENX.
Since these interactions of ENX with TP observed in rats are similar to those reported in humans, the magnitude of interactions of other pyridonecarboxylic acids with TP are possibly predictable by the methods described.
