Modeling of aceclofenac metabolism to major metabolites in healthy volunteers

Purpose: Aceclofenac used widely as a NSAID is converted to 4-hydroxyaceclofenac and diclofenac via cytochrome P450 2C9-mediated hydroxylation and hydrolysis, respectively. CYP2C9 also mediates the hydroxylation of diclofenac to yield 4-hydroxydiclofenac and the hydrolysis of 4-hydroxyaceclofenac to 4-hydroxydiclofenac. We analyzed the pharmacokinetics of aceclofenac and the sequential formation of its three metabolites using a compartmental modeling approach.

Methods: Following an administration of aceclofenac 100 mg in healthy volunteers, blood sample was serially taken and plasma concentrations of aceclofenac and its three metabolites were measured using LC/MS/MS. Time courses of plasma concentrations of 4 substances were modeled by ADAPT 5.

Results: The delay parameter (Tau=0.2 h) shifted the plasma aceclofenac concentration–time profile to the right and provided a large improvement of fit, especially during the absorption phase and around the maximum concentration of aceclofenac. The absorption rate constant, k_a, was 0.65 h^–1 in the absence of the time delay, and the correlation coefficient (r²) was 0.82. A steep absorption rate constant (0.95 h^–1) was obtained with Tau, and r² increased to 0.96.

Two compartments were needed to fit the aceclofenac and 4-hydroxyaceclofenac data, and one additional compartment was sufficient to describe the time courses of the generated plasma concentrations of diclofenac and 4-hydroxydiclofenac.

The metabolism rate constant for 4-hydroxyaceclofenac (k_m,4OH-ace, 0.72 h^–1) was estimated to be much greater than that for diclofenac (k_m,diclo, 0.04 h^–1). In the same manner, the generation rate constant of 4-hydroxydiclofenac from diclofenac (k_m,Fdiclo, 0.46 h^–1) was greater than that of its generation from 4-hydroxyaceclofenac (k_m,F4OH-ace, 0.01 h^–1).

Aceclofenac and its metabolites were simulated following multiple administration of aceclofenac 100 mg twice daily.

Conclusion: Our model fully describes the time course of plasma aceclofenac concentration as well as the formation and disposition of its three major metabolites in healthy volunteers.