REDUCED TETRACYCLINE BIOAVAILABILITY CAUSED BY MAGNESIUM ALUMINUM SILICATE IN LIQUID FORMULATIONS OF BISMUTH SUBSALICYLATE

RATIONALE: Bismuth subsalicylate, tetracycline hydrochloride, and metr onidazole are widely used in combination for the treatment of Helicoba cter pylori infections. As a result, there is renewed interest in the interaction between tetracycline and bismuth subsalicylate. OBJECTIVE: To determine whether the observed decrease in tetracycline bioavailab ility is due to the active drug bismuth subsalicylate via complexation , or to magnesium aluminum silicate (Veegum), an inactive excipient pr esent only in the liquid formulation of bismuth subsalicylate, which m ight adsorb the tetracycline, rendering it unavailable for systemic ab sorption. METHODS: Eleven healthy volunteers participated in a randomi zed three-period, three-treatment complete crossover study with a 7-da y washout interval between treatments. After an overnight fast, subjec ts received a 500-mg capsule of tetracycline hydrochloride with either tap water, 30 mt of bismuth subsalicylate (525 mg) liquid containing Veegum (Pepto-Bismol), or 30 mt of a specially formulated bismuth subs alicylate (525 mg) liquid without Veegum. Blood was collected for 24 h ours after each dose of tetracycline. Serum was assayed for tetracycli ne concentration by HPLC. In addition, standard in vitro ultraviolet s pectrophotometric methods were used to determine the capacity for comp lexation of bismuth with tetracycline and for adsorption of tetracycli ne to Veegum. RESULTS: Compared with the reference treatment of tetrac ycline hydrochloride with water, the liquid formulation of bismuth sub salicylate containing Veegum decreased the maximum serum concentration (C-max) of tetracycline by 21% and the serum tetracycline AUC by 27% (p < 0.001). The bismuth subsalicylate formulation without Veegum resu lted in decreases in C-max and AUC of 11% and 13%, respectively (p > 0 .05 vs, tetracycline hydrochloride with water). Multiple linear regres sion analysis of the spectral absorbance data demonstrated a calculate d recovery of tetracycline of 100.9% and, therefore, a lack of in vitr o complexation with bismuth. At pH 1.2, the amount of tetracycline ads orbed to Veegum ranged from 91.5% to 97.2% over the concentration rang e of 0.25 to 2 mg/mL. At pH 7.0, the values ranged from 82.9% to 83.9% over the concentration range of 0.25 to 1 mg/mL. CONCLUSIONS: In vitr o and in vivo data from this study indicate that Veegum, a suspending agent, and not the active agent bismuth subsalicylate, is the primary ingredient in liquid formulations of bismuth subsalicylate responsible for a decrease in tetracycline bioavailability. In addition, the mech anism of interaction is not likely due to complexation between tetracy cline and bismuth subsalicylate, as previously postulated, but rather is caused by adsorption of tetracycline to the excipient Veegum, which is present only in the liquid formulation of bismuth subsalicylate. T he clinical relevance of this interaction has not been determined.