摘要：The pharmacokinetics of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9) and its metabolites were studied in rats and humans. Appropriate equations describing models for rats and humans were fitted to the plasma (and urine) data using a non-linear least-squares analysis. 1. Rats : After intravenous administration (2.5 mg/kg) of 14C-DKA-9 to rats, the concentration of DKA-9 and 5-carboxymethyl-4'-chloro-3-biphenylyl hydrogen sulfate (DKA-24S) in plasma were both described by the two compartment model ; the half lives of hybrid rate constants [(t1/2) α and (t1/2) β] and the volume of the central compartment were 0.424, 2.91 hr and 0.101 L/kg for DKA-9, and 0.295, 8.07 hr and 0.129 L/kg for DKA-24S, respectively. Urinary excretion (% of dose) of radioactivity was 87.8±1.3% (mean±S.D., n=3) and 99% of which corresponded to DKA-24S. However, the concentration of 4'-chloro-5-hydroxy-3-biphenylylacetic acid (DKA-24), which is the precursor of DKA-24S, was found to be negligible in most of plasma, urinary, and fecal samples, therefore, this metabolite was neglected in the kinetic study. 2. Humans : When DKA-9 was administered orally to seven healthy male subjects, DKA-9 absorption and disposition did not virtually show a dose-dependency at doses of 42.8 and 85.5 mg : DKA-9 was absorbed from a gastro-intestinal tract with the half life [(t1/2)ka] of 0.525±0.129 hr (n=7) after the lag time (tlag) of 0.526±0.266 hr ; the maximum concentration (Cmax) of DKA-9 was 3.1±0.1 (n=3) and 5.5±0.4 μg/ml (n=4), and the area under the DKA-9 plasma concentration-time curve in 0-8 hr ([AUC]0-8hr) was 6.85±0.54 and 13.1±0.9 μg·hr/ml after administration of 42.8 and 85.5 mg, respectively. Urinary excretion of DKA-9 and its metabolites (% of dose, n=4) were : DKA-9 (≒0), DKA-24 (≒0), 4'-chloro-5-methoxy-3-biphenylylacetyl β-D-glucopyranosiduronic acid (DKA-9G) (60.1±6.0%), 4'-chloro-5-hydroxy-3-biphenylylacetyl β-D-glucopyranosiduronic acid (DKA-24G) (8.1±0.4%), DKA-24S (13.9±0.4%), 5-carboxymethyl-4'-chloro-3-biphenylyl β-D-glucopyranosiduronic acid (DKA-24OG) (6.5±0.6%), and 2-(4'-chloro-5-methoxy-3-biphenylyl)-2-hydroxyacetic acid (αOH-DKA-9) (1.3±1.2%). Urinary excretion rate constants of DKA-9G and DKA-24G were found to be much greater in magnitude than those of DKA-24S and DKA-24OG, which suggests that acylglucuronides could be more easily excreted from plasma due to a lesser degree of plasma protein binding.
