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 r at jejunum. Metabolism experiments were performed with everted sacs, wherea s sheets mounted in a symmetrical twin chamber system were used in transpor t studies. DTZ was rapidly desacetylated by the rat jejunum to the principl e metabolite desacetyl-diltiazem (M1). In addition, minor amounts of N-deme thyl-diltiazem and desacetyl-N-demethyl-diltiazem were formed. Due to the r apid desacetylation, it proved difficult to study the transport of DTZ in t his 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 dir ection. Both coadministration of verapamil and Pgp monoclonal antibody dose dependently increased luminal-to-serosal flux and decreased serosal-to-lum inal flux. In conclusion, rat jejunum metabolizes DTZ extensively in vitro, and the major primary metabolite M1 is subjected to Pgp-mediated efflux.