The disposition of tiludronate in mouse, rat, rabbit, dog and monkey has been studied after oral and intravenous doses. Like other bisphosphonates, tiludronate was characterized by poor absorption from the gastrointestinal tract. Peak plasma concentrations appeared shortly (0.5-1 h) after dosing, except for the baboon (4.5 h). Food intake highly impaired intestinal absorption The affinity of tiludronate for bone and the slow release from this deep compartment could account for the large volume of distribution and the low plasma clearance found in all species. Tiludronate has low affinity for red blood cells and binds moderately to serum proteins, mainly to serum albumin. Calcified tissues appeared to be the main target for deposition. Distribution into bone was not homogenous, with higher levels in the trabecular bone than in the corticol part of the long bones. The uptake of tiludronate into bone was unequivocally less in the older animal. No metabolism occurred in the tested animal species. The major route of elimination of the absorbed drug is urine. Preclinical observations made with tiludronate, like with other bisphosphonates, were predictive of results obtained in clinical investigation.
The pharmacokinetics and the effect of ticlopidine on platelet aggregation were determined in patients with chronic renal failure (n = 6), who were not on dialysis and had glomerular filtration of 16.9 +/- 4.4 mL/min, and were matched with the pharmacokinetics and effects in healthy volunteers (n = 7). Participants were studied after acute oral administration of ticlopidine at the beginning of the study and after 36 days of treatment with 250 mg twice daily. For unchanged ticlopidine there were no significant differences between the concentration profiles for the two study groups. By day 36 the minimum concentrations in plasma were identical (0.35 +/- 0.22 mg/L and 0.36 +/- 0.21 mg/L, respectively). Using 14C-labeled ticlopidine, the concentration profiles of radioactivity on day 1 were similar to those on day 36 for both groups. However, maximum concentrations and area under the concentration-time curve at 72 hours were both higher in patients with renal failure than in healthy volunteers. Treatment with ticlopidine progressively decreased sensitivity to adenosine diphosphate-induced platelet aggregation. At day 36, the concentration of adenosine diphosphate required to achieve 50% platelet aggregation was approximately 2.5 times greater than before treatment. Both patients and healthy volunteers exhibited closely comparable changes. The response to collagen-induced platelet aggregation was not changed in patients by treatment with ticlopidine. In contrast, volunteers required a three- to fourfold increase in collagen concentration to achieve 50% platelet aggregation after 36 days of therapy. Although some differences in both pharmacokinetics and pharmacodynamics of ticlopidine have been demonstrated between patients and and healthy volunteers, results in this study demonstrated that a change of dosage is not required in renal failure.
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