Clearance and tissue uptake following 4-hour and 24-hour infusions of pamidronate in rats.
Bisphosphonates are clinically useful for the treatment of bone disorders; however, there is some controversy concerning the extent to which the design of the dosage regimen influences the efficacy of these drugs. The effect of different rates of infusion of [14C] pamidronate (APD; 3-amino-1-hydroxy-propylidene-1,1-bisphosphonate) (1 mg/kg infused over 4 or 24 hr) on its pharmacokinetics was investigated in rats by the measurement of tissue disposition and plasma clearance. The pharmacokinetic parameters, including total clearance, renal clearance, and nonrenal clearance, were found to be not significantly affected by the rate of infusion. The concentration of pamidronate in tibia, liver, kidney, and spleen was also unaffected by the two infusion rates. The bone (tibia) contained the highest concentration of all the tissues sampled, and the kidney accumulated the highest concentration among the soft tissues measured; this was in contrast to previous bolus administration studies where the liver and spleen contained higher concentrations than the kidney. The disposition kinetics of pamidronate were found to be essentially multiphasic, with a rapid initial half-life that gradually tails into a very long terminal phase. A terminal half-life could not be reliably estimated as it increased with time. As a consequence a model-independent approach, based on the calculation of the total, renal, and nonrenal clearance, best served to describe the disposition kinetics of pamidronate. For this unmetabolized compound the nonrenal clearance can be ascribed to tissue binding, which appears to be essentially irreversible.(ABSTRACT TRUNCATED AT 250 WORDS)
Pongchaidecha
M
M
Department of Pharmacy, University of Manchester, UK.
Daley-Yates
P T
PT
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D004164:Diphosphonates / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D000077268:Pamidronate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004164:Diphosphonates; D000077268:Pamidronate