CONCOMITANT ADMINISTRATION OF CHOLESTYRAMINE INFLUENCES THE ABSORPTION OF TROGLITAZONE

Troglitazone is an orally active anti-diabetic agent. Cholestyramine i s an orally administered lipid-lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclini cal studies suggesting the potential for an interaction between trogli tazone and cholestyramine require confirmation in a clinical setting. Methods In vitro and in vivo experiments in the dog were carried out p rior to a clinical study. Twelve healthy volunteers (mean age 32, year s, range 20-44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazo ne) in an open, two-way crossover study. Results In vitro, about 99% o f troglitazone was adsorbed by cholestyramine at an incubate concentra tion of 3 mu g ml(-1) whilst at 500 mu g ml(-1) adsorption fell to abo ut 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 mu g ml(-1) h (95% CI for difference 28-57, P=0.01) in 1 1 beagle dogs receiving troglitazone 200 nle and cholestyramine 1 g co mpared with control values. Mean maximum plasma concentration (C-max) was 49% of control values (7.08 vs 3.42 mu g ml(-1) (95% CI for differ ence 14-85, P=0.05)). In the clinical study median AUC for troglitazon e and its two major metabolites were statistically significant lower w hen troglitazone was administered with cholestyramine (17.9 vs 5.2 mu g ml(-1) h (95% CI for difference -20.5, -8.7), 133.7 vs 27 1 mu g ml( -1) h (-166.4, -67.8) and 18.4 vs 2.5 mu g ml(-1) h (-21.6, -10.6) for troglitazone, sulphate and quinone metabolite respectively (all P<0.0 1) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in C-max for th e sulphate metabolite (4.56 vs 1.28 mu g ml(-1) (95% CL for difference -4.42, -1.99, P < 0.01)), but not for troglitazone (1.85 vs 1.23 mu g ml (-1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 mu g ml(-1 ) (-0.77, 0.09)). Conclusions The results were indicative of an altera tion in the extent of troglitazone's absorption. Concomitant administr ation of troglitazone and cholestyramine could severely impair troglit azone's clinical utility as an antihyperglycaemic agent.