Nonlinear kinetics of alendronate. Plasma protein binding and bone uptake

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. The purpose of this study was to examine the plasma protein binding and the ability of bone to bind alendronate, and their effects on the distribution of the drug to bone tissues. In addition, the species differences in plasma protein binding and bone uptake between rats and dogs were studied. Following intravenous administration (0.8 or 1 mg/kg), the apparent uptake clearance (CL,up) by tibia in dogs and rats was approximately 0.075 and 0.18 ml/min/g bone tissue, respectively. The binding of alendronate to plasma protein was species-dependent; the drug was highly bound to rat plasma, but not to dog plasma. The unbound fraction of alendronate was approximately 0.03 for the rat and 0.53 for the dog. Binding studies with purified serum albumin revealed the presence of displacer(s) in dog plasma. This may explain the low binding of alendronate in dog plasma. Like other organs, uptake of drugs by bone tissue is controlled by the plasma flow (Q), the fraction of unbound drug in plasma (fp), and the intrinsic ability of bone to bind the drug (CLin) as described by the equation: CL,up = Q(1-e-tp.CLin/Q). Plasma flow to the tibia of dogs and rats is reported to be approximately 0.09 and 0.25 ml/min/g, respectively. By applying the equation, the CLin was estimated to be approximately 10 ml/min/g for the rat and 0.3 ml/min/g for the dog. These results indicate that both plasma protein binding and bone uptake were species-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)