Metabolite inhibition of parent drug biotransformation. Studies of diltiazem

Previously, we have demonstrated in vivo, in humans, nonlinear diltiazem disposition with an elimination half-life 50-100% greater after chronic diltiazem as compared to single-dose diltiazem administration. At least two metabolites, desmethyldiltiazem (M(A)) and desacetyldiltiazem (M₁), accumulate significantly in human plasma during chronic diltiazem administration. To test the hypothesis that nonlinear diltiazem accumulation is associated with inhibition of biotransformation, we studied diltiazem disappearance during incubation with a number of its identified metabolites in an isolated rat hepatocyte system. Apparent k(i)s for disappearance of diltiazem were: M(A), 88.3 μM; M₁, 608 μM; M₂ (desacetyl N-desmethyldiltiazem), 495 μM; M₄ (desacetyl O-desmethyldiltiazem), 152 μM; and M₆ (desacetyl N,O-desmethyldiltiazem), 448 μM. These apparent k(i) values are similar to those derived for diltiazem-mediated inhibition of other drug substrates such as antipyrine, the clearance of which is inhibited by diltiazem in vivo in humans. Nonlinear diltiazem accumulation in vivo may be explained in part by progressive metabolite accumulation, particularly M(A), which results in the inhibition of parent drug diltiazem biotransformation.