Theophylline and Antiparasitic Drug Interactions: RESULTS
The mean age of the subjects was 28 ± 3 years; mean weight, 69.6 ±2.9 kg; and mean height, 175.2 ±4.5 cm.
Data collection was completed in only three of the six subjects during thiabendazole administration. Two subjects experienced severe nausea, vomiting and dizziness during concurrent thiabendazole and theophylline administration. The third subject experienced only severe nausea. Due to the severity of these side effects it was decided to discontinue the amino- phylline-thiabendazole study arm and report data on three subjects. There were no adverse reactions experienced during the mebendazole phase of the study.
Theophylline clearance was significantly decreased from a mean of0.067 ± 0.016 to 0.023 ± 0.0058 L/h/kg during steady-state thiabendazole therapy (p = 0.0032). The mean total Cl for theophylline alone was 0.067 ±0.016 L/h/kg. There was no significant difference in theophylline clearance during steady-state mebendazole therapy.
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FIGURE 1. Concentrations in plasma of theophylline after the administration of a 6 mg/kg intravenous bolus of aminophylline over 30 min alone and repeated with concurrent administration of either thiabendazole or mebendazole in one representative subject (open circle, baseline theophylline phase; open square, concomitant theophylline and thiabendazole; and open triangle, concomitant theophylline and mebendazole).
Theophylline mean volume of distribution was different (p = 0.0468) during administration of thiabendazole. Mean theophylline volume of distribution was and a pressure of 1,500 lb/ sq in. Betahydroxyethyltheophylline (Sigma Chemical Co, St Louis, MO) was used as the internal standard. Standards of known theophylline concentration were 0.63 ± 0.042 L/kg prior to administration of interac- tant. During steady-state thiabendazole therapy, the mean theophylline volume of distribution decreased to 0.59 ± 0.083 L/kg while it increased to 0.67 ± 0.035 L/kg with concomitant administration of mebendazole.
Baseline theophylline elimination rate constant was 0.11 ±0.027 h-1. The elimination rate constant decreased significantly to 0.039 ±0.010 h-1 during thiabendazole administration (p = 0.0028). There was no significant difference detected in theophylline elimination rate constant during mebendazole therapy (Table 2). The theophylline concentration vs time curves which illustrate the alteration in theophylline elimination during thiabendazole administration in one representative subject are presented in Figure 1.
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Theophylline mean half-life was significantly (p = 0.0016) increased from a baseline value of 6.72±1.47 h to 18.60±5.63 h during concomitant administration of thiabendazole. Mebendazole failed to significantly alter the theophylline mean half-life.