In vitro adsorption of bile salts and aspirin to sucralfate.

Sucralfate, an aluminum salt of sulfated sucrose, is a new drug designed for the treatment of peptic ulcer. Sucralfate has been reported to be useful in a variety of situations including prevention of aspirin-induced gastric mucosal damage. We investigated the in vitro adsorption of bile salts or aspirin to sucralfate in environments simulating the stomach (pH 1.5), small intestine (pH 7), and colon (pH 7.8). Bile salts were incubated with sucralfate, and the quantity of bile salt adsorbed was calculated by subtraction from the amount remaining in solution after centrifugation at 12,500g for 30 min. Adsorption experiments were performed in bile salt solutions at pH 1.5 and 7.0 with 0-10 g/dl sucralfate using glycocholate, glycochenodeoxycholate, taurocholate, taurodeoxycholate, or taurochenodeoxycholate. The dihydroxy-unconjugated bile salts, deoxycholic, and chenodeoxycholic salts were tested at pH 7.8. Binding capacity (micromoles per gram sucralfate) was calculated from the linear regression of micromoles bound vs grams sucralfate incubated. Sucralfate adsorbed all bile salts tested (except taurocholic acid at pH 1.5) but was less effective than cholestyramine. Sucralfate does not adsorb sufficient bile salts at neutral pH to cause bile salt depletion. Aspirin was minimally adsorbed by sucralfate [7.5 mumol (1.4 mg)/g sucralfate, pH 1.5], and thus adsorption of aspirin does not explain the protective effect of sucralfate against aspirin injury.

Quantitation of diltiazem and desacetyldiltiazem in dog plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic procedure was developed for the determination of diltiazem and desacetyldiltiazem in dog plasma. Two milliliters of plasma is extracted with a hexane-2-propanol mixture. The assay uses a reverse-phase column maintained at 55 degrees C with a silica saturation column and a pellicular precolumn. The mobile phase is acetonitrile-water (50:50) at pH 6.6 with 1.5-g/L heptanesulfonic acid added as the ion-pair reagent. The procedure is sensitive to 5 ng/mL for both compounds in dog plasma and is linear up to 2000 ng/mL for diltiazem and 1000 ng/mL for desacetyldiltiazem . Preliminary dog mean plasma profiles of diltiazem and desacetyldiltiazem are presented.

Pharmacokinetics of diltiazem in selected animal species and human beings.

The absorption, distribution and elimination of diltiazem hydrochloride in rodent and canine species are reviewed. The drug is well absorbed but undergoes first pass metabolism after oral administration. Diltiazem is extensively distributed, and 52 to 81 percent is bound to serum protein, depending on the species studied. Diltiazem is metabolized in the liver by several pathways; deacetylation, N-demethylation, and O-demethylation are the primary degradative steps. The metabolites are excreted in urine and feces, indicating that biliary excretion occurs. There is some evidence for enterohepatic cycling. Diltiazem is rapidly eliminated (t 1/2 = 2.24 hours) in beagle dogs, and the relatively short half-life appears to be a result of the high level of plasma clearance (46.1 +/- 4.8 ml/min/per kg body weight). A comparison of the plasma diltiazem clearance with hepatic blood flow in the dog indicates that the drug is eliminated at a rate dependent on hepatic blood flow.