Limitations to the oral absorption of cyclosporine A.

Abstract

The long term goal of this work is to understand the relative contributions of the various barriers to the oral absorption of peptides and proteins. These barriers include acid hydrolysis in the stomach, enzymatic attack by gastric, pancreatic, and mucosal enzymes, an inherent lack of membrane permeability, and first pass metabolism. Cyclosporine A (CsA) was chosen as our model compound in the study of peptide drug absorption for many reasons. Although CsA has many structural features and physical properties that set it apart from typical peptides, it is one of the few that is absorbed to a significant degree from the gastrointestinal tract. It should therefore be possible to identify and weigh the relative importance of the factors which limit its absorption. A further reason for studying CsA is that its variable and incomplete absorption leads to clinically significant problems in terms of preventing transplant rejection while avoiding adverse effects. Identification of the limitation(s) to oral absorption may therefore aid in the design of better formulations and/or dosing regimens for CsA. The specific objective of this research was to identify the factor(s) which limit the oral absorption of CsA. Several factors which may limit the absorption of CsA from the oral formulation have been identified. These include precipitation when the oral solution dosage form is diluted/administered, slow (re)dissolution in the upper gastrointestinal tract, the need for bile salt assisted dissolution, poor membrane permeability, and metabolism by both the gut wall and liver. Our results indicated that solubility related factors are an important limitation to the oral absorption of CsA. Significant quantities (30%-50% of the dose) were shown to precipitate from the oral solution when diluted with an aqueous medium. This effect was shown to be temperature dependent, being more pronounced at body temperature than under refrigerated conditions. Dissolution was shown to be very slow at simulated intestinal pH, with some enhancement when physiologically relevant quantities of bile salts were added. Therefore, it appears that solubility, via its effects on precipitation and dissolution, is an important limiting factor to the oral absorption of CsA. Uptake experiments using intestinal rat rings as the experimental model showed that uptake of CsA is not limited by the permeability of the mucosa to CsA, with concentration-normalized uptake rates comparable to those of compounds with good oral bioavailability. Recent literature on the enzyme system responsible for the metabolism of CsA (cytochrome P450IIIA) indicated that intestinal and hepatic metabolism also contribute to the interindividual variation in CsA bioavailability. Quantitative data on the rate of metabolism of CsA by intestinal cytochrome P450IIIA is necessary before the relative importance of physicochemical and metabolic limitations to CsA absorption can be assessed.