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Pharmacokinetic–Pharmacodynamic Modeling of the Hydroxy Lerisetron Metabolite L6-OH in Rats: An Integrated Parent–Metabolite Model

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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 μg 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 (Fc = 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 (CpL6) generated after a lerisetron therapeutic dose (10 μg kg−1) in the rat. These concentrations are needed for the PD model and are below the quantification limit. CpL6max 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.

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Acknowledgments

Funding for this study was provided in part by the Ministry of Science and Technology of Spain (PROFIT 2000–2003) and the Department of Industry, Commerce and Tourism of the Basque Government (INTEK 2002), and also by a UPV group grant (9/UPV 00026-327-14593/2002). One of the authors (F.O.) was funded by a Gangoiti Foundation fellowship.

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Correspondence to Rosario Calvo.

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Ortega, F., Quintana, A., Suárez, E. et al. Pharmacokinetic–Pharmacodynamic Modeling of the Hydroxy Lerisetron Metabolite L6-OH in Rats: An Integrated Parent–Metabolite Model. Pharm Res 22, 1769–1782 (2005). https://doi.org/10.1007/s11095-005-7750-6

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  • DOI: https://doi.org/10.1007/s11095-005-7750-6

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