Concomitant administration of cholestyramine influences the absorption of troglitazone.
OBJECTIVE
Troglitazone is an orally active anti-diabetic agent. Cholestyramine is an orally administered lipid-lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclinical studies suggesting the potential for an interaction between troglitazone and cholestyramine require confirmation in a clinical setting.


METHODS
In vitro and in vivo experiments in the dog were carried out prior to a clinical study. Twelve healthy volunteers (mean age 32 years, range 20-44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazone) in an open, two-way crossover study.


RESULTS
In vitro, about 99% of troglitazone was adsorbed by cholestyramine at an incubate concentration of 3 microg ml(-1) whilst at 500 microg ml(-1) adsorption fell to about 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 microg ml(-1) h (95% CI for difference 28-57, P=0.01) in 11 beagle dogs receiving troglitazone 200 mg and cholestyramine 1 g compared with control values. Mean maximum plasma concentration (Cmax) was 49% of control values (7.08 vs 3.42 microg ml(-1) (95% CI for difference 14-85, P=0.05)). In the clinical study median AUC for troglitazone and its two major metabolites were statistically significantly lower when troglitazone was administered with cholestyramine (17.9 vs 5.2 microg ml(-1) h (95% CI for difference -20.5, -8.7), 133.7 vs 27 1 microg ml(-1) h (-166.4, -67.8) and 18.4 vs 2.5 microg ml(-1) h (-21.6, -10.6) for troglitazone, sulphate and quinone metabolite respectively (all P < 0.01) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in Cmax for the sulphate metabolite (4.56 vs 1.28 microg ml(-1) (95% CI for difference -4.42, -1.99, P < 0.01)), but not for troglitazone (1.85 vs 1.23 microg ml(-1) (-1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 microg ml(-1) (-0.77, 0.09)).


CONCLUSIONS
The results were indicative of an alteration in the extent of troglitazone's absorption. Concomitant administration of troglitazone and cholestyramine could severely impair troglitazone's clinical utility as an antihyperglycaemic agent.
Young
M A
MA
Department of Clinical Pharmacokinetics and Dynamics, Glaxo Wellcome Research and Development Ltd, Greenford, Middlesex, UK.
Lettis
S
S
Eastmond
R
R
D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002792:Cholestyramine Resin / Q000494:pharmacology*; D002839:Chromans / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004285:Dogs; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D013844:Thiazoles / Q000493:pharmacokinetics*; D045162:Thiazolidinediones; D000077288:Troglitazone
D000924:Anticholesteremic Agents; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D002792:Cholestyramine Resin; D000077288:Troglitazone