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The effect of bile acids on atenolol bioavailability was assessed using a randomised two-way cross-over study in eight healthy volunteers. Single dose kinetics were studied in fasted subjects using either Tenormin® or a preparation of atenolol containing bile acids. The co-administration of bile acids with atenolol resulted in a 30% reduction in AUC and a 28% reduction in Cmax compared to Tenormin®. No significant differences in tmax or t 1 2 were detected. The potential clinical implications of the interactions between atenolol and bile acids in vivo are discussed, together with a possible explanation for the observed effects of food on atenolol bioavailability.

Propranolol, a clinically proven lipophilic β-adrenergic blocking agent, undergoes extensive and unpredictable first-pass hepatic metabolism when administered as a conventional oral formulation. A nine-subject three-way cross-over study was performed in healthy human volunteers to assess the relative bioavailability of two novel oral formulations of propranolol, designed to bypass hepatic first-pass metabolism. These formulations contained a mixture of unsaturated fatty acids, mainly oleic acid, and surfactants in enteric-coated liquid-filled hard gelatin capsules. Using these formulations selective increases of up to more than 6-fold in AUC and 4-fold in C max were achieved in subjects who responded poorly to Inderal ® . The increased propranolol bioavailability achieved using the liver by pass formulations was associated with a reduction in the coefficient of variance for both C max and AUC of up to 44%, when compared to Inderal ® . The results of the present study suggest the possibility of developing a predictable reduced dose delivery system for basic lipophilic drugs which undergo extensive hepatic first-pass metabolism.

A drug delivery system has been designed which uses non-ionic surfactants to enhance the dissolution and adsorption of poorly soluble lipophilic drugs, vitamins and fat-soluble nutrients. Vitamin E absorption using this system, was shown to be independent of food intake in a healthy human volunteer study. Stability studies using formulations containing vitamin E or vitamin E and β-carotene indicated that the incompatibility normally encountered when using hard gelatin capsules with non-ionic surfactants may be overcome by including small amounts of glycerol and water.

The effect of exogenously added bile acids upon the bioavailability of indomethacin was investigated in healthy human volunteers. In vitro dissolution studies were performed on formulations containing indomethacin and bile acids and the effects of enteric coating determined. Pharmacokinetic evaluation of the results of the human volunteer study suggests that bile acids increase the bioavailability of indomethacin by prolonging its enterohepatic circulation. The relevance of the findings to drug delivery system for anionic drugs is discussed. A rapid and efficient means of determining indomethacin in human plasma, using solid-phase extraction, is described.