Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine*

TLDR

Cyclosporine’s low and variable bioavailability is largely due to poor absorption, but intestinal first‑pass metabolism also contributes significantly. The study aims to develop theory and methods to separate the effects of oral absorption, intestinal, and hepatic metabolism on cyclosporine bioavailability. The authors apply boundary‑condition analysis to existing laboratory data to estimate absorption and extraction ratios. Analysis shows that cyclosporine absorption is at least 65 % in healthy volunteers and 77 % in kidney transplant patients, with gut extraction roughly twice hepatic extraction, and that 86 % of the drug is absorbed intact from the commercial product, indicating that absorption is not the limiting factor and that the boundary‑condition approach can broadly differentiate bioavailability determinants.

Abstract

The low and variable bioavailability of cyclosporine has been attributed to poor absorption. However, recent studies have suggested that intestinal first-pass metabolism exerts a significant effect on bioavailability. We describe theory and methods to differentiate the contribution from oral absorption and intestinal and hepatic metabolism to overall cyclosporine bioavailability. Analysis of data from previous studies in our laboratories shows that in the absence of intestinal metabolism, cyclosporine absorption from its presently available dosage form averages 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 commercially available product in healthy volunteers. The boundary condition analysis described should have broad application in the differentiation of factors responsible for poor bioavailability.