Mebendazole

To determine a change in theophylline pharmacokinetics during concomitant thiabendazole or mebendazole therapy, we studied six normal, healthy male volunteers. Aminophylline was administered intravenously, followed by a 30-h blood sampling period. Subjects were randomized to receive thiabendazole or mebendazole, then crossed over to receive the other therapy. Theophylline concentrations were measured utilizing an HPLC technique and a one-compartment model was fit to the data. Theophylline pharmacokinetic parameters were significantly different during thiabendazole therapy. Mean theophylline half-life increased, clearance decreased and elimination rate constant decreased. Two subjects experienced severe nausea and vomiting during thiabendazole therapy. There were no significant differences in theophylline pharmacokinetic parameters during mebendazole therapy. Thiabendazole administration results in a significant decrease in theophylline clearance and beta elimination rate constant. The theophylline half-life increased significantly. Concomitant administration of theophylline and thiabendazole resulted in severe nausea and vomiting. Mebendazole administration did not seem to alter theophylline pharmacokinetics.

Mebendazole and thiabendazole are benzimidazole compounds used in the treatment of parastic infections.[1] Patients with asthma who have immigrated from areas endemic with Strongyloides may have exacerbations of their asthma with Strongyloides migration up the tracheobronchial tree. These patients may be treated with theophylline and if Strongyloides is found in stool or sputum specimens, thiabendazole may be added to their treatment.

There have been two well documented cases of a theophylline-thiabendazole interation.[2,3] In the first case, the theophylline concentration rose from 105 [mu]mol/L (19 [mu]g/ml) to 255 [mu]mol/L (46 [mu]g/ml) during thiabendazole therapy.[2] Toxic theophylline concentrations were avoided in the second case by reducing the theophylline dose by 33 percent initially, then again to 50 percent of the patient's initial dose.[3]

There have been no reported cases of a mebendazole-theophylline interaction. However, we present another well documented case of theophylline toxicity due to the addition of thiabendazole. This prompted us to perform a normal human volunteer study on the effects of steady-state thiabendazole or mebendazole on single-dose theophylline pharmacokinetics.

CASE REPORT

A 64-year-old Puerto Rican man (height, 160 cm; weight, 64 kg) was admitted to the hospital on December 25 with an exacerbation of asthma. He was afebrile but had a cough productive of thin white sputum. His chest radiograph was normal. The arterial blood gas values were pH, 7.44; [PCO.sub.2], 34; [CO.sub.2] content, 24; [PO.sub.2], 73; and oxygen saturation, 95 percent. Theophylline concentration was less than 14 [mu]mol/L (2.5 mg/L) and the CBC was 7,600 WBC with 55 percent polymorphonuclear leukocytes, 15 percent eosinophils, 1 percent basophils, 22 percent lymphocytes and 7 percent monocytes. Liver function tests were normal throughout the hospitalization. There was no history of cardiac disease and the patient had not used tobacco for many years. Aminophylline was given as a 300 mg intraveous bolus with a continous infusion at 30 mg/h. Due to his eosinophilia, stool and sputum were analyzed for ova and parasites. On December 29, it was reported that the stool was positive for the rhabdoid larvae of S stercoralis. The sputum culture was negative. The theophylline concentration was 100 [mu]mol/l (18 mg/L) on December 29 at an aminophylline infusion rate of 30 mg/h half-life of 16 h and clearance of 1.3 L/h). Thiabendazole was started that evening at 1.5 g orally twice a day. On the morning of December 30, the theophylline concentration was 105 [mu]mol/L (19 mg/L). On December 31, the patient was complaining of nausea and a headache. The theophylline concentration was 144 [mu]mol/L (26 mg/L). The theophylline half-life increased to 33 h and clearance had decreased to 0.65 L/h. The aminophylline infusion was discontinued, then restarted at a decreased rate of 20 mg/h. The thiabendazole was discontinued due to development of a skin rash and pyrantel pamoate was substituted. A seven- to ten-day course of antiparasitic therapy was planned because the patient was receiving steroids. The patient was discharged January 6 on a regimen of Theo-Dur, 200 mg orally twice a day, with a theophylline concentration of 44 [mu]mol/L (8 mg/L). No ova or parasites were found in the patient's stool specimen of January 6. [TABULAR DATA OMITTED]

METHODS

Six nonsmoking, adult, male volunteers participated in the study. Each subject was judged to be in good health on the basis of a physical examination, clinical laboratory testing, and ECG. These data can be found in Table 1. The study was an open label, randomized, crossover design. All subjects signed an informed consent approved by the institutional review committee.

Aminophylline (25 mg/ml for injection), thiabendazole (500-mg chewable tablets, Mintezol) and mebendazole (100-mg tablets, Vermox) were used.

Phase 1

Subjects abstained from alcohol and methylxanthine-containing food and beverages for 48 h prior to the aminophylline infusion. Utilizing an IMED infusion pump (IMED Corp, San Diego, CA) a 6 mg/kg intravenous dose of aminophylline was administered over 30 min in all subjects.

Blood samples were collected prior to the aminophylline infusion and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 30 h after completion of the infusion.

Phases 2 and 3

Following a one-week washout period, subjects were randomized to receive either thiabendazole or mebendazole. Thiabendazole, 1.5 g, or mebendazole, 100 mg, was taken orally (every 12 h) for six doses. The aminophylline infusion and sampling period were repeated 1 h after the fourth dose of thiabendazole or mebendazole, as described in the baseline phase. After this phase, the subjects were then crossed over to receive the other therapy. Blood sampling an aminophylline infusion were repeated as described in phase 1.

Sample Analysis

Plasma samples were analyzed for theophylline by a modified reverse phase, HPLC technique.[4] A Waters C-18 column and Waters model 440 UV absorbance detector (wavelength 280 nm) were utilized (Waters Corp, Milford, MA). Column elution was carried out with a flow rate of 1 ml/min and a pressure of 1,500 lb/sq in. Bethydroxyethyltheophylline (Sigma Chemical Co, St Louis, MO) was used as the internal standard. Standards of known theophylline concentration were prepared in pooled human serum ranging in concentration from 1.4 to 112 [mu]mol/L (0.25 to 20 mg/L). The standard curve was linear and reproducible within this range. Unknown concentrations were determined by a peak-height ratio technique. The sensitivity limit was 1.4 [mu]mol/L (0.25 [mu]g/ml). Reproducibility measurements yielded inter-day variability of 3 to 6 percent. [TABULAR DATA OMITTED]

Pharmacokinetic Analysis

The decline in the theophylline postdistributive plasma concentrations for all subjects was monoexponential, characterized by a one-compartmental model. The independent pharmacokinetic parameters of clearance and volume of distribution were modeled using an iterative least-squares program.

Statistical Analysis

Statistical analysis of the resultant kinetic parameters was performed utilizing a univariate two-way ANOVA accounting for subject and treatment effects (Table 2). An alpha level of less than 0.05 was considered significant. When a significant difference was detected, Tukey's multiple range test was used for comparisons among means.

RESULTS

The mean age of the subjects was 28 [+ or -] 3 years; mean weight, 69.6 [+ or -] 2.9 kg; and mean height, 175.2 [+ or -] 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 experience only severe nausea. Due to the severity of these side effects it was decided to discontinue the aminophylline-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 of 0.067 [+ or -] 0.016 to 0.023 [+ or -] 0.0058 L/h/kg during steady-state thiabendazole therapy (p = 0.0032). The mean total Cl for theophylline alone was 0.067 [+ or -] 0.016 L/h/kg. There was no significant difference in theophylline clearance during steady-state mebendazole therapy.

Theophylline mean volume of distribution was different (p = 0.0468) during administration of thiabendazole. Mean theophylline volume of distribution was 0.63 [+ or -] 0.042 L/kg prior to administration of interactant. During steady-state thiabendazole therapy, the mean theophylline volume of distribution decreased to 0.59 [+ or -] 0.083 L/kg while it increased to 0.67 [+ or -] 0.035 L/kg with concomitant administration of mebendazole.

Baseline theophylline elimination rate constant was 0.11 [+ or -] 0.027 h[-1]. The elimination rate constant decreased significant to 0.039 [+ or -] 0.10 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.

Theophylline mean half-life was significantly (p = 0.0016) increased from a baseline value of 6.72 [+ or -] 1.47 h to 18.60 [+ or -] 5.63 h during concomitant administration of thiabendazole. Mebendazole failed to significantly alter the theophylline mean half-life.

DISCUSSION

The toxicity of theophylline is serum concentration-dependent.[5,6] Several physiologic factors and therapeutic agents alter theophylline pharmacokinetics, resulting in an increase in a patient's serum theophylline concentration.[6-9]

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, hydroxylation and N-demethylation.[10] There are many commercially available and investigational imidazole/benzimidazole drugs such as cimetidine,[11] ketoconazole,[12] metronidazole,[13] etomidate,[14] itraconazole[15] and omeprazole[16] 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 lipophilicity of the substituted imidazoles facilitates penetration of lipid membranes and hydrophobic bonding to cytochrome P450.[11]

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 mamimum 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).[17] A second confounding factor is that mebendazole is decarboxylated,[18] not hydroxylated or N-demethylated. The change is 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 [mu]mol/L (15 [mu]g/ml).[5] Theophylline concentrations during this phase were less than 66 [mu]mol/L (12 [mu]g/ml). Thiabendazole has been shown to cause nausea and vomiting in 66 percent of patients.[19] Theophylline-induced nausea and vomiting has occurred in patients receiving aminophylline intravenously,[20] suggesting a direct stimulation of the central nervous system. Thiabendazole also has been shown to cross the blood-brain barrier into the cerebrospinal fluid.[21] Possibly the nausea and vomiting experienced by our subjects was induced by the central action of theophylline and thiabendazole.

CONCLUSIONS

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.

REFERENCES

[1] Warren KS. Diseases due to helminths. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and practices of infectious disease. 2nd ed. New York: John Wiley and Sons, 1985:1562-68

[2] Sugar AM, Kearns PJ, Haulk AA, Rushing JL. Possible thiabendazole induced theophylline toxicity. Am Rev Respir Dis 1980; 122:501-03

[3] Lew G, Murray WE, Lane R, Haeger E. Theophylline-thiabendazole drug interaction. Clin Pharm 1989; 8:225-27

[4] Orcutt JJ, Kozak PP, Gillman SA, Cummins LH. Micro-scale method for theophylline in body fluids by reverse-phase, high pressure liquid chromatography. Clin Chem 1977; 23:599-601

[5] Jacobs MH, Senior RM, Kessler G. Clinical experience with theophylline: relationships between dosage, serum concentration and toxicity. JAMA 1976; 235:1983-86

[6] Hendeles L, Weinberger M. Theophylline: a "state of the art" review. Pharmacotherapy 1983; 3:2-44

[7] Zarowitz BJM, Szefler SJ, Lasezkay GM. Effect of erythromycin base on theophylline kinetics. Clin Pharmacol Ther 1981; 29:601-05

[8] Burnakis TG, Seldon M, Czaplicki AD. Increased serum theophylline concentrations secondary to oral verapamil. Clin Pharm 1983; 2:458-61

[9] Weinberger MW, Hudgel D, Spector S, Chidsey C. Inhibition of theophylline clearance by troleandomycin. J Allergy Clin Immunol 1977; 59:228-31

[10] Wilkinson CF, Hetnarski K, Yellin TO. Imidazole derivatives--a new class of microsomal enzyme inhibitors. Biochemical Pharmacol 1972; 21:3187-92

[11] Campbell MA, Plachetka JR, Jackson JE, Moon JF, Finley PR. Cimetidine decreases theophylline clearance. Ann Intern Med 1981; 95:68-69

[12] Brown MW, Maldonado AL, Meredith CG, Speeg KV. Effect of ketoconazole on hepatic oxidative drug metabolism. Clin Pharmacol Ther 1985; 37:290-97

[13] O'Reilly RA. The stereo selective interaction of warfarin and metronidazole in man. N Engl J Med 1976; 295:354

[14] Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenisis by the anesthetic etomidate. N Engl J Med 1984; 310:1415-21

[15] Trenk D, Brett W, Jahnchen E, Birnbaum D. Time course of cyclosporin/itraconazole interaction. Lancet 1987; 2:1335-36

[16] Gugler R, Jensen JC. Omeprazole inhibits oxidative drug metabolism. Gastroenterology 1985; 89:1235-41

[17] Keystone S, Murdoch JK. Mebendazole. Ann Intern Med 1979; 91:582-86

[18] Brugmans JP, Theinpont DC, Van Wijngaarden I, Vanparijo OF, Schuermans VL, Lauwers HL. Mebendazole in enterobiasis radiochemical and pilot clinical study in 1,278 subjects. JAMA 1971; 217:313-16

[19] Grove DI. Treatment of strongyloidiasis with thiabendazole: an analysis of toxicity and effectiveness. Trans R Soc Trop Med Hyg 1982; 76:114-18

[20] Kordash TR, VanDellen RG, Mc Call JT. Theophylline concentrations in asthmatic patients: after administration of aminophylline. JAMA 1977; 238:139-41

[21] Arroyo JC, Brown A. Concentrations of thiabendazole and parasitic-specific IgG antibodies in the cerebral spinal fluid of a patient with disseminated strongyloidiasis. J Infect Dis 1987; 156:520-23

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