PURPOSE: Diltiazem (DTZ) undergoes extensive metabolism yielding several metabolites, some of which retain a certain degree of pharmacological activity. N-demethylating activity has been detected mainly in the liver. Nevertheless, the organs involved in the formation of the deacetylated metabolite of DTZ (M1) have not been fully elucidated. In order to address this issue, we have carried out in vitro studies using the blood, lung, brain, small intestine, and liver as enzyme sources. METHODS: DTZ (1,000 ng/ml) was incubated in 10,000 x g supernatant homogenates of selected tissues or in whole blood for 240 minutes at 37 degrees C. Multiple samples were withdrawn, and DTZ and its metabolite M1 were assayed by HPLC. RESULTS: The apparent degradation rate constant of DTZ was in the rank order blood > lung > brain > liver > small intestine. This trend can also be observed for the AUC and for the percentage of DTZ metabolized. In all the tissue homogenates examined there was a net production of the deacetylated metabolite. The M1 metabolite was also detected in the blood (500 ng/ml after 240 minutes of incubation). CONCLUSIONS: The widespread distribution of the DTZ deacetylase activity described in this study suggests that extrahepatic metabolism of DTZ to M1 may play a relevant role in the overall pharmacokinetics of DTZ.
PURPOSE:Diltiazem (DTZ) undergoes extensive metabolism yielding several metabolites, some of which retain a certain degree of pharmacological activity. N-demethylating activity has been detected mainly in the liver. Nevertheless, the organs involved in the formation of the deacetylated metabolite of DTZ (M1) have not been fully elucidated. In order to address this issue, we have carried out in vitro studies using the blood, lung, brain, small intestine, and liver as enzyme sources. METHODS:DTZ (1,000 ng/ml) was incubated in 10,000 x g supernatant homogenates of selected tissues or in whole blood for 240 minutes at 37 degrees C. Multiple samples were withdrawn, and DTZ and its metabolite M1 were assayed by HPLC. RESULTS: The apparent degradation rate constant of DTZ was in the rank order blood > lung > brain > liver > small intestine. This trend can also be observed for the AUC and for the percentage of DTZ metabolized. In all the tissue homogenates examined there was a net production of the deacetylated metabolite. The M1 metabolite was also detected in the blood (500 ng/ml after 240 minutes of incubation). CONCLUSIONS: The widespread distribution of the DTZ deacetylase activity described in this study suggests that extrahepatic metabolism of DTZ to M1 may play a relevant role in the overall pharmacokinetics of DTZ.
Authors: L Pichard; G Gillet; I Fabre; I Dalet-Beluche; C Bonfils; J P Thenot; P Maurel Journal: Drug Metab Dispos Date: 1990 Sep-Oct Impact factor: 3.922
Authors: S Nakamura; T Suzuki; Y Sugawara; S Usuki; Y Ito; T Kume; M Yoshikawa; H Endo; M Ohashi; S Harigaya Journal: Arzneimittelforschung Date: 1987-11
Authors: R Bernasconi; S Caliari; R Latini; D Leopaldi; S Porzio; A Salimbeni Journal: Eur J Drug Metab Pharmacokinet Date: 1992 Oct-Dec Impact factor: 2.441