Pharmacokinetic Interactions between Erythromycin, Clarithromycin, Roxithromycin and Phenytoin in the Rat

Abstract

The effects of the macrolide antibiotics, erythromycin, clarithromycin and roxithromycin, on the pharmacokinetic profile of phenytoin were studied in rats. Animals were injected with phenytoin (100 mg/kg, i.p.) daily for 4 days and then they were given phenytoin (20 mg/kg, i.p.) alone or the same dose of phenytoin together with erythromycin (50 mg/kg, i.p.), clarithromycin (50 mg/kg, i.p.) or roxithromycin (50 mg/kg, i.p.). In another set of experiments, the same protocol was followed except that erythromycin (100 mg/kg), clarithromycin (100 mg/kg) and roxithromycin (100 mg/kg) were given by the oral route. The concentrations of phenytoin in plasma were determined using a high-performance liquid chromatographic method. The area under the curve the maximum plasma concentration and the elimination half-life (t_½) of phenytoin were significantly (p < 0.05) increased by the macrolides. In addition, the macrolides significantly (p < 0.05) reduced the level of hepatic cytochrome P-450 in the rats. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with erythromycin, clarithromycin or roxithromycin.

Drug-induced CYP-induction as therapy for tacrolimus intoxication

“…In contrast to rifampicin, however, phenytoin is primarily metabolized by CYP enzymes and is particularly susceptible to inhibitory drug interactions [ 7 ]. A study in rats showed that clarithromycin increases phenytoin AUC and elimination half-life significantly [ 17 ]. On one hand, this may lead to increased phenytoin bioavailability in CYP-inhibited environments, on the other hand, phenytoin elimination kinetics may be difficult to predict, and adverse reactions may arise.…”