Effects of Ticlopidine on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats

pharmacokinetic studies of diltiazem. CYP3A4, a key enzyme in the metabolism of diltiazem is mainly located in liver, but it is also expressed in the small intestine (Watkins et al., 1987; Pichard et al., 1990; Kolars et al., 1992). Thus, diltiazem could be metabolized in both the small intestine and the liver (Homsy et al., 1995a; Homsy et al., 1995b; Lefebvre et al., 1996). Lee et al. (1991) reported that the extraction ratios of diltiazem in the small intestine and the liver after oral administration to rats were about 85% and 63%, respectively, indicating that diltiazem is highly extracted in the small intestine and the liver. In addition to the extensive metabolism, P-glycoprotein (Pgp) may also lower the bioavailability of diltiazem. Yusa and Tsuruo (1989) reported that calcium channel blockers such as verapamil and diltiazem competitively restrained the multidrug resistance of P-gp. Wacher et al. (2001) also suggested that diltiazem is a substrate of both CYP3A4 and P-gp. Since P-gp is co-localized with CYP3A4 in the small intestine, P-gp and CYP3A4 may act synergistically in the presystemic drug Original Article Biomol Ther 19(2), 255-260 (2011)