DIFFERENTIATION OF ABSORPTION AND FIRST-PASS GUT AND HEPATIC-METABOLISM IN HUMANS - STUDIES WITH CYCLOSPORINE

The low and variable bioavailability of cyclosporine has been attribut ed to poor absorption. However, recent studies have suggested that int estinal first-pass metabolism exerts a significant effect on bioavaila bility. We describe theory and methods to differentiate the contributi on from oral absorption and intestinal and hepatic metabolism to overa ll cyclosporine bioavailability. Analysis of data from previous studie s in our laboratories shows that in the absence of intestinal metaboli sm, cyclosporine absorption from its presently available dosage form a verages at least 65% +/- 12% in healthy volunteers and 77% +/- 19% in kidney transplant patients. Analysis also suggests that the extraction ratio for cyclosporine in the gut is approximately twice the hepatic extraction and that cyclosporine absorption does not present a problem , with an average of 86% of the drug absorbed intact from its commerci ally available product in healthy volunteers. The boundary condition a nalysis described should have broad application in the differentiation of factors responsible for poor bioavailability.