Cholestyramine influences the absorption of troglitazone
Troglitazone, 4-thiazolidinedione, is an insulin action enhancing agent under clinical development for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). Administration with, or up to 30 min after, food significantly improves absorption of troglitazone due probably to enhanced bile solubilisation and dissolution time.
Cholestyramine is an anion exchange resin with lipid-lowering properties. Taken orally, it is not absorbed from the gastrointestinal tract but is excreted unchanged in the faeces. Cholestyramine lowers LDL-cholesterol by binding to bile acids and preventing their enterohepatic circulation.
Therefore, because of the physicochemical properties of troglitazone, investigations were undertaken to determine the influence of concomitant administration of cholestyramine on the pharmacokinetics of troglitazone.
Preclinical studies
An in vitro study using [14C]-troglitazone, in conditions mimicking the small intestine in vivo, was conducted to determine the adsorption of troglitazone by cholestyramine. [14C]-troglitazone was dissolved in ethanol to give a solution used to spike 3 and 500 μg ml−1 incubates of solutions of human serum albumin (HSA) prepared in Sorensen’s buffer pH 6. HSA was used to increase the aqueous solubility of the drug and to mimic food proteins in the gut. The percentage loss (P) of soluble radiolabel from each test incubate compared with the appropriate control was used as a measure of absorption. This was determined from the following equation: 
where Rc=mean radioactivity concentration in the control incubate supernatant (d min−1/200 μl) and Rt=mean radioactivity concentration in the corresponding test incubate supernatant (d min−1/200 μl).
Cholestyramine (4×1 g) was administered once, 1 h prior to receiving a single oral tablet of troglitazone 200 mg, and on three occasions 1, 2 and 4 h post-dose, as an aqueous suspension (1 g in 10 ml water) by gavage to 11 Beagle dogs. Blood sampling was carried out from the cephalic vein at 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h following administration. Plasma samples were assayed by reversed phase h.p.l.c. with u.v. detection as previously described. A paired t-test was used to compare previously obtained (control) AUC (area under the plasma concentration time curve), Cmax (maximum observed plasma concentration) and tmax (time at which Cmax was reached) values for each dog with corresponding values obtained from this study.
Clinical study
Study methodology has been described elsewhere. Twelve healthy subjects each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (3×4 g sachets) in random order as part of an open, two-way crossover study. Troglitazone was taken 30 min after a standardized breakfast and cholestyramine was given as an aqueous solution 1 h after ingestion of troglitazone. Blood samples were taken pre-dose and at 15, 30, 45, 60, and 90 min and 2, 3, 4, 6, 8, 12, 24, and 48 h post-dose.
Pharmacokinetic parameters, Cmax, tmax, t1/2 (elimination half-life) and AUC were calculated for troglitazone and its main metabolites as described previously.
The normal parametric method was not used in these analyses because one subject was reported with no absorption of troglitazone and therefore, a zero value for AUC; thus log transformation was not possible. The pharmacokinetic parameter values for AUC, Cmax, and tmax for troglitazone, sulphate and quinone metabolites were analysed using Koch’s non-parametric method based on the Wilcoxon Rank Sum test. An estimate of the median difference between troglitazone with cholestyramine and troglitazone alone, together with a 95% confidence interval was calculated. Subjects for whom it was not possible to calculate tmax due to poor absorption were excluded from the analysis of tmax. The analysis of t1/2 for troglitazone and sulphate metabolite was performed following log transformation using analysis of variance allowing for subjects, periods and treatments. Subjects for whom it was not possible to calculate t1/2 due to a poorly defined terminal elimination phase were excluded from the analysis of t1/2.
Filed under: Clinical Pharmacology