TY - JOUR T1 - Drug-Induced Hemodynamic Perturbations Alter the Disposition of Markers of Blood Volume, Extracellular Fluid, and Total Body Water JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 922 LP - 930 VL - 296 IS - 3 AU - Tom C. Krejcie AU - Zhao Wang AU - Michael J. Avram Y1 - 2001/03/01 UR - http://jpet.aspetjournals.org/content/296/3/922.abstract N2 - Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine facilitate description of intravascular mixing and tissue distribution following intravenous administration. These models characterized physiologic marker disposition in four awake dogs under control conditions and during phenylephrine, isoproterenol, and nitroprusside infusions. Systemic vascular resistance was more than doubled by phenylephrine and was decreased more than 50% by both isoproterenol and nitroprusside. Dye (ICG) dilution cardiac output (CO) was decreased nearly one-third by phenylephrine, was more than doubled by isoproterenol, and was largely unaffected by nitroprusside. Although phenylephrine reduced CO, the fraction of CO represented by nondistributive blood flow nearly doubled at the expense of blood flow to rapidly equilibrating tissues. The area under the blood antipyrine concentration versus time relationship for 3 min after administration (AUC0–3 min) during the phenylephrine infusion was nearly 75% larger than control due to both increased first-pass AUC and an increased fraction of CO represented by nondistributive blood flow. The large increase in CO produced by isoproterenol increased blood flow to rapidly equilibrating tissues and relatively decreased blood flow to slowly equilibrating tissues, because some appeared to equilibrate rapidly. Antipyrine AUC0–3 min during the isoproterenol infusion decreased more than 30%, due to decreased first-pass AUC. Nitroprusside changed antipyrine intercompartmental clearances in proportion to CO and, hence, had little effect on antipyrine AUC0–3 min. These data provide further evidence that changes in antipyrine (a lipophilic drug surrogate) blood flow-dependent distribution after rapid i.v. administration arenot proportional to changes in CO but depend on both CO and its distribution. The American Society for Pharmacology and Experimental Therapeutics ER -