The metabolic extraction of diltiazem was examined in conjunction with its absorption, using rat small intestine perfused in situ by the single-pass method, to clarify its intestinal metabolism. This is a topic of increasing interest which has not been fully clarified, particularly as far as the extent of metabolic extraction and the enzymes involved (cytochrome P450 (CYP) 3A and/or others) are concerned. The intestinal availability (Fi) of diltiazem was evaluated at steady-state by dividing the fraction absorbed into the mesenteric venous blood (Fa,b) by the fraction that disappeared from the intestinal lumen (Fa). The Fi of diltiazem (0.05 mM) was 0.126 and, hence, the extraction ratio (Ei=1-Fi) was 0.874, indicating that diltiazem undergoes extensive first-pass metabolism during its passage through the intestinal mucosa. The Ei was unchanged when the concentration was increased to 0.5 mM, suggesting that metabolism is linear over this concentration range. Thereafter, Ei decreased with concentration, demonstrating saturable metabolism, and reached an insignificant level at the highest concentrations of 30 and 50 mM. The decrease in Ei, or increase in Fi, was brought about by an increase in Fa,b (from about 0.02 to about 0.05) in the concentration range up to 10 mM and by a decrease in Fa (from about 0.15 to about 0.05) at concentrations higher than that. These results suggest that the extraction observed at the lower concentrations is almost solely attributable to metabolic extraction of a saturable nature. However, ketoconazole and cyclosporin A, which are specific CYP3A inhibitors, inhibited the metabolic extraction of diltiazem (0.05 mM) by only about 20% at the concentration (40 microM) at which they inhibited CYP3A almost completely, suggesting that the contribution of CYP3A to intestinal diltiazem metabolism is not marked. Thus, the present study demonstrates that diltiazem undergoes extensive first-pass metabolism in the rat small intestine, although the contribution of CYP3A seems to be relatively minor.