Pharmacokinetics of alendronate

Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate) h as demonstrated effectiveness orally in the treatment and prevention of pos tmenopausal osteoporosis, corticosteroid-induced osteoporosis and Paget's d isease of the bone. Its primary mechanism of action involves the inhibition of osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of alendronate must be interpreted in the context of its unique properties , which include targeting to the skeleton and incorporation into the skelet al matrix. Preclinically, alendronate is not metabolised in animals and is cleared fro m the plasma by uptake into bone and elimination via renal excretion. Altho ugh soon after administration the drug distributes widely in the body, this transient state is rapidly followed by a nonsaturable redistribution to sk eletal tissues. Oral bioavailability is about 0.9 to 1.8%, and food markedl y inhibits oral absorption. Removal of the drug from bone reflects the unde rlying rate of turnover of the skeleton. Renal clearance appears to involve both glomerular filtration and a specialised secretory pathway. Clinically, the pharmacokinetics of alendronate have been characterised alm ost exclusively based on urinary excretion data because of the extremely lo w concentrations achieved after oral administration. After intravenous admi nistration of radiolabelled alendronate to women, no metabolites of the dru g were detectable and urinary excretion was the sole means of elimination. About 40 to 60% of the dose is retained for a long time in the body, presum ably in the skeleton, with no evidence of saturation or influence of one in travenous dose on the pharmacokinetics of subsequent doses. The oral bioavailability of alendronate in the fasted state is about 0.7%, with no significant difference between men and women. Absorption and dispos ition appear independent of dose. Food substantially reduces the bioavailab ility of oral alendronate; otherwise, no substantive drug interactions have been identified. The pharmacokinetic properties of alendronate are evident pharmacodynamical ly. Alendronate treatment results in an early and dose-dependent inhibition of skeletal resorption, which can be followed clinically with biochemical markers, and which ultimately reaches a plateau and is slowly reversible up on discontinuation of the drug. These findings reflect the uptake of the dr ug into bone, where it exerts its pharmacological activity, and a time cour se that results from the long residence time in the skeleton. The net resul t is that alendronate corrects the underlying imbalance in skeletal turnove r characteristic of several disease states. In women with postmenopausal os teoporosis, for example, alendronate treatment results in increases in bone mass and a reduction in fracture incidence, including at the hip.