Pharmacokinetic-pharmacodynamic modeling of the hydroxy lerisetron metabolite L6-OH in rats:: An integrated parent-metabolite model

Purpose. The twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro pharmacological activity, and evaluate the extent to which L6-OH contributes to the overall effect. Methods. The PK of L6-OH was determined directly postmetabolite i.v. dose (PK-1), and also simultaneously for L (lerisetron concentration) and for generated L6-OH after lerisetron dose (200 mu g kg(-1), i.v.), using Nonlinear Mixed Effects Modeling with an integrated parent-metabolite PK model (PK-2). Surrogate effect was measured by inhibition of serotonin-induced bradycardia. Protein binding was assayed via ultrafiltration and all quantification was performed via liquid chromatography-electrospray ionization-mass spectrometry. Results. L6-OH showed elevated plasma and renal clearances, and volume of distribution (PK-1). The in vivo potency (PD) of L6-OH was high (EC50 = 0.098 ng mL(-1) and EC50unbound = 0.040 ng mL(-1)). Total clearance for L (PK-2) in the presence of generated L6-OH (CLL = CL-->L6-OH + CLn) was 0.0139 L min(-1). Most of this clearance was L6-OH formation (F-c = 99.6%), but only an 8.6% fraction of L6-OH was released into the bloodstream. The remainder undergoes biliar and fecal elimination. The parameters estimated from PK-2 were used to predict concentrations of L6-OH (Cp-L6) generated after a lerisetron therapeutic dose (10 mu g kg(-1)) in the rat. These concentrations are needed for the PD model and are below the quantification limit. Cp-L6max was less than the EC50 of L6-OH. Conclusions. We conclude that after lerisetron administration, L6-OH is extensively formed in the rat but it is quickly eliminated; therefore, besides being equipotent with the parent drug, the L6-OH metabolite does not influence the effect of lerisetron.