Theophylline and Antiparasitic Drug Interactions: DISCUSSION
The toxicity of theophylline is serum concentration- dependent. Several physiologic factors and therapeutic agents alter theophylline pharmacokinetics, resulting in an increase in a patients serum theophylline concentration.
The basis for an interaction is found in the fact that imidazole/benzimidazole compounds are potent inhibitors of hepatic microsomal enzymes, specifically the cytochrome P-450 reactions of epoxidation, hydroxy- lation and N-demethylation. There are many commercially available and investigational imidazole/benzimidazole drugs such as cimetidine, ketoconazole, metronidazole, etomidate, itraconazole and omeprazole which have been documented to inhibit cytochrome P-450 and thereby cause drug interactions.
Theophylline is metabolized through the hepatic microsomal enzymes. Thiabendazole and mebendazole are benzimidazole compounds. The greater lipo- philicity of the substituted imidazoles facilitates penetration of lipid membranes and hydrophobic bonding to cytochrome P450.
Our results demonstrate a significant increase in theophylline half-life and a significant decrease in theophylline clearance, and elimination rate constant during concomitant administration of thiabendazole. The change in theophylline clearance and half-life is probably due to inhibition of the hepatic microsomal enzymes by thiabendazole.
While the ANOVA detected a difference among the theophylline volume of distribution means, the significance was marginal (p = 0.0468). However, the absolute change was small and probably would not result in a substantial alteration in theophylline serum concentrations.
A significant difference was detected in theophylline maximum concentration among the groups but neither treatment was found to be different from baseline theophylline maximum concentration.
The statistical significance detected in the volume of distribution and maximum concentration during thiabendazole administration is probably the result of a beta error. The power of the test would be low due to the very small sample size.
No statistical difference in theophylline clearance or half-life was detected in the mebendazole phase of the study. It was determined that a much larger study population is necessary to establish significance. The small change in theophylline clearance and half-life may be the result of insufficient interactant concentrations because mebendazole is poorly absorbed from the gastrointestinal tract (5 to 10 percent). A second confounding factor is that mebendazole is decarbox- ylated, not hydroxylated or N-demethylated. The change in clearance and half-life is relatively small and probably not clinically significant.
All subjects tolerated the baseline aminophylline infusion. Severe nausea and vomiting were experienced during the thiabendazole phase. Nausea and vomiting can occur within the normal therapeutic range for theophylline, but usually not until the theophylline concentration is greater than 83 jimol/L (15 jig/ml). Theophylline concentrations during this phase were less than 66 jimol/L (12 ^g/ml). Thiabendazole has been shown to cause nausea and vomiting in 66 percent of patients. Theophylline-induced nausea and vomiting has occurred in patients receiving aminophylline intravenously, suggesting a direct stimulation of the central nervous system. Thiabendazole also has been shown to cross the blood-brain barrier into the cerebrospinal fluid. Possibly the nausea and vomiting experienced by our subjects was induced by the central action of theophylline and thiabendazole. Viagra Soft Tabs
Thiabendazole administration results in a significant decrease in theophylline clearance and elimination rate constant. A significant increase occurred in the theophylline half-life, potentially as a result of inhibition of the mixed function oxidase system.
Concomitant administration of theophylline and thiabendazole resulted in severe nausea and vomiting requiring the administration of an antinauseant.
Mebendazole administration does not seem to alter theophylline pharmacokinetics, probably as a result of poor systemic absorption and alternate pathways for mebendazole metabolism.