Renal handling of warfarin metabolites in man

The present study examines the mechanism of renal clearance of two major warfarin metabolites, S-7-hydroxywarfarin and R,S-warfarin alcohol, in three healthy subjects who each received 1.5 mg/kg rac-warfarin alone (control) or in combination with phenylbutazone (PBZ). The unbound fraction of warfarin metabolites (fu(m)) was predicted using the unbound fraction of warfarin enantiomers determined, using equilibrium dialysis at 37 degrees C and an enantioselective HPLC assay. In the control phase the unbound renal clearance (CLuR) ranged from 182 to 583 ml/min (mean, 318) for S-7-hydroxywarfarin and from 23 to 191 ml/min (mean, 96) for R,S-warfarin alcohol. For S-7-hydroxywarfarin CLuR was much greater than the glomerular filtration rate (GFR) indicating that this metabolite undergoes net secretion in the kidney. In two subjects CLuR for R,S-warfarin alcohol was less than GFR indicating that this metabolite undergoes net tubular reabsorption. The CLuR in each subject for both metabolites was notably lower during the coadministration of PBZ (39 to 62 ml/min for S-7-hydroxywarfarin and 5 to 17 ml/min for R,S-warfarin alcohol) suggesting that this drug inhibits renal secretion of these metabolites. The inhibition of renal secretion of metabolites by PBZ allows an estimation of the minimum fraction of filtered metabolite that undergoes reabsorption, being 86% to 90% for R,S-warfarin alcohol and 51% to 69% for S-7-hydroxywarfarin. The difference is probably explained by the greater polarity of S-7-hydroxywarfarin. Analysis also indicates that under control conditions secretion is a major component of renal excretion for both metabolites, accounting for 80% and 84% of metabolite entering the renal tubules for S-7-hydroxywarfarin and R,S-warfarin alcohol, respectively.