Mechanisms of time-dependent kinetics of diltiazem in the isolated perfused rat liver.

The time-dependent mechanisms of diltiazem (DZ) disposition were studied in a single-pass isolated perfused rat liver system. DZ (2-100 microM) was infused continuously until a steady state was achieved. The time required to achieve steady state (Tss) ranged from 15 to 75 min and was inversely related to infusion concentration. Steady-state extraction (E) of DZ decreased from 0.98 to 0.73 as the outlet concentration increased from 0.03 to 26.34 microM. This reduction of E is not related to the saturation of the primary deacetylation and N-demethylation pathways of metabolism. The N-demethylated metabolite went through a characteristic maximum prior to reaching a steady state, indicating enzyme inactivation. During a second DZ infusion, spaced with a 30-min washout period (stop-infusion experiment), the concentration vs. time profile of DZ was similar to that of the first one. Washout data from stop-infusion and [3H]DZ infusion studies showed that DZ and its metabolites were tightly bound to liver proteins. This observation is consistent with the unusually long Tss of DZ. Infusion studies with [3H]DZ showed that 669.5 +/- 156.5 and 974.2 +/- 99.2 nmol of DZ and its metabolites (calculated as DZ) were bound and/or distributed/g of liver at inlet concentrations of 35.5 +/- 3.2 and 67.2 +/- 3.4 microM, respectively. The amounts of DZ and its metabolites bound irreversibly to the whole liver, hepatic microsomal and hepatic cytosolic proteins were not different at the two inlet concentrations studied and were 24.5 +/- 6.6, 48.8 +/- 11.8, and 23.7 +/- 5.8 pmol/mg of protein, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)