Pharmacokinetics of @entity2379 in XXXX as a function of dose following constant-rate intravenous infusion.

@entity8 @entity2379 @entity364 @entity1011 @entity35 @entity11015
@entity2379 ( @entity11015 ) is widely used for the treatment of systemic @entity364 . The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of @entity11015 as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male @entity35 were given different two-step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three @entity11015 doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 +/- 0.33, 0.86 +/- 0.24, and 0.37 +/- 0.04 mL min-1 kg-1 for the low-medium and high-dose groups, respectively; p < 0.05). Signs of @entity8 were observed in the high-dose group, as documented by decreased @entity1011 clearance. Dose-dependent renal clearance may have been due either to nephrotoxicity associated with the high dose of @entity11015 and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time-averaged values (based on the estimation of area under the plasma concentration-time profile). This suggests that clearance calculations from time-averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of @entity11015 and to reach steady state tissue concentration to confirm the estimation of systemic clearance.
