Abstract

We investigated the pharmacokinetics of YM175, a new bisphosphonate, after intravenous and oral administrations in rats and dogs. After intravenous administration at 0.03-0.3 mg/kg, plasma YM175 concentration declined biexponentially with an apparent terminal half-life of 0.37-0.72 hr in rats and 3.30-4.09 hr in dogs. In both species, the area under the plasma concentration vs. time curve increased dose-proportionally, whereas volume of distribution at steady-state and total body clearance changed little among doses, indicating the linear pharmacokinetics of the drug after intravenous administration. After oral administration to rats (3-30 mg/kg) and dogs (0.3-10 mg/kg), maximum concentration and area under the plasma concentration vs. time curve increased more than dose-proportionally at 30 mg/kg in rats and at 3 mg/kg or higher in dogs. Thus, bioavailability increased at higher doses, being 1.0%, 1.2%, and 3.6% at 3, 10, and 30 mg/kg in rats, and being 1.8%, 1.3%, 2.9%, and 11.5% at 0.3, 1, 3, and 10 mg/kg in dogs, respectively. Urinary excretion and bone concentration of radioactivity in rats receiving [14C]YM175 agreed well with those of unchanged drug in both administration routes, and radiochromatograms of rat urine revealed no peaks of metabolites. These findings suggest that YM175 undergoes practically no metabolism and indicate that the increase in bioavailability at higher doses is caused by enhanced drug absorption, and not by any saturation of first-pass metabolism. Finally, concentrations of YM175 in the rib of dogs receiving a 0.3 mg/kg intravenous dose were highest in the epiphyseal costa, followed by the middle costa and cartilage, indicating that the uptake of YM175 into bone is site-dependent. Furthermore, the drug in rib decreased biexponentially with a terminal half-life of 249 days in the epiphyseal costa and 351 days in the middle costa, suggesting that the elimination rate of YM175 from bone is also site-dependent.