Extensive metabolism of diltiazem and P-glycoprotein-mediated efflux of desacetyl-diltiazem (M1) by rat jejunum in vitro.

The objective of this in vitro study was to investigate both the intestinal metabolism and transport of diltiazem (DTZ) and its major metabolites in rat jejunum. Metabolism experiments were performed with everted sacs, whereas sheets mounted in a symmetrical twin chamber system were used in transport studies. DTZ was rapidly desacetylated by the rat jejunum to the principle metabolite desacetyl-diltiazem (M1). In addition, minor amounts of N-demethyl-diltiazem and desacetyl-N-demethyl-diltiazem were formed. Due to the rapid desacetylation, it proved difficult to study the transport of DTZ in this model. However, the primary metabolite M1 was shown to be subjected to P-glycoprotein (Pgp)-mediated efflux. The flux rate of M1 was 6- to 7-fold higher from the serosal to the luminal compartment than in the opposite direction. Both coadministration of verapamil and Pgp monoclonal antibody dose dependently increased luminal-to-serosal flux and decreased serosal-to-luminal flux. In conclusion, rat jejunum metabolizes DTZ extensively in vitro, and the major primary metabolite M1 is subjected to Pgp-mediated efflux.