Lin J H, Chen I W, Deluna F A
Merck Research Laboratories, West Point, PA 19486.
Drug Metab Dispos. 1993 Sep-Oct;21(5):800-4.
Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. Earlier studies in rats from this laboratory have demonstrated that systemically administered alendronate was taken up by bone tissues to the extent of 60-70% of the dose and excreted by the kidneys, 30-40%, and that renal excretion was the only route of elimination of the drug. In this study, a classic three-compartment model was used to determine the kinetics of bone uptake of alendronate in hypo- and hypercalcemic rats. Following intravenous administration (1 mg/kg), the apparent uptake clearance (CL,up) by tibia was approximately 0.18 ml/min/g of bone for control rats, 0.25 ml/min/g for hypocalcemic rats, and 0.05 ml/min/g for hypercalcemic rats. Like other organs, uptake of drugs by bone tissues would be controlled by the plasma flow rate (Q), the fraction of unbound drugs in plasma (fp), and the intrinsic ability of bone uptake (CLin) as described by the equation: CL,up = Q(1 - e-fp.CLin/Q). The plasma flow rate to the tibia of rats was reported to be approximately 0.25 ml/min/g. The unbound fraction of alendronate in plasma of control, hypo-, and hypercalcemic rats was 0.03, 0.45, and 0.035, respectively. By applying the equation, the intrinsic ability (CLin) of bone uptake was estimated to be approximately 10, 2.3, and 1.6 ml/min/g for control, hypo-, and hypercalcemic rats, respectively, indicating that the intrinsic ability of bone to bind alendronate was decreased in both hypo- and hypercalcemic rats.
