Absorption, distribution, metabolism and excretion of [14C]levocetirizine, the R enantiomer of cetirizine, in healthy volunteers.

The main goal of the present study was to investigate the absorption and disposition of levocetirizine dihydrochloride, the R enantiomer of cetirizine dihydrochloride, following a single oral administration (5 mg) of the 14C-labelled compound in healthy volunteers. Configurational stability was also investigated. Levocetirizine was rapidly and extensively absorbed: 85.4% and 12.9% of the radioactive dose were recovered 168 h post-dose in urine and faeces, respectively. Levocetirizine and/or its metabolites were not, or only very poorly, associated with blood cells, as the blood-to-plasma ratio was 0.51 to 0.68. The mean apparent volume of distribution (Vz/F) was 26.9 1 (0.3 l/kg) indicating that the distribution of levocetirizine is restrictive. The protein binding of radiolabelled levocetirizine was 96.1% l h after administration. In vitro, at concentrations ranging from 0.2 microg/ml to 1 microg/ml, the protein binding was 94.8% to 95.0%. Levocetirizine is very poorly metabolised. The cumulative 48-h excretion as parent compound accounted for 85.8% of the oral dose, equivalent to 95% of the total radioactivity excreted at this time. At least 13 minor metabolites were detected in urine and represented 2.4% of the dose at 48 h. The metabolic pathways involved in levocetirizine metabolism are oxidation (hydroxylation, O-dealkylation, N-oxidation and N-dealkylation), glucuroconjugation, taurine conjugation and glutathione conjugation with formation of the mercapturic acids. There was no evidence of chiral inversion of levocetirizine in humans. This result is consistent with that obtained in preclinical studies.