Pharmacokinetics of bisphosphonates in rabbits.

Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The 14C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P < 0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P = 0.016). At 24 hr, plasma concentration of tiludronate was 12 +/- 6.6%, of etidronate 18 +/- 2.5%, of clodronate 0.8 +/- 0.2%, and of pamidronate 1.4 +/- 0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC0-24 hr for tiludronate and etidronate was 9-11 times larger than for clodronate. AUC0-24 hr for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9-15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2-1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of tiludronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates.