The Concordance of Early Antipyrine and Thiopental Distribution Kinetics
- Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Dr. Michael J. Avram, Department of Anesthesiology, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Avenue, Ward Building 13-199, Chicago, IL 60611-3008. E-mail: mja190{at}northwestern.edu
Abstract
Studies of factors affecting the initial disposition of drugs with a rapid onset of effect following i.v. administration have used antipyrine as a surrogate for lipophilic drugs because it lacks cardiovascular effects. The present study tested the assumption that antipyrine is a useful surrogate for the flow-dependent tissue distribution of the lipophilic drug thiopental by comparing the recirculatory pharmacokinetic models of antipyrine and thiopental disposition after concomitant administration to five dogs anesthetized with 1.5% halothane. The pharmacokinetics of indocyanine green, a marker of the intravascular behavior of antipyrine and thiopental, and antipyrine in these dogs was nearly identical to that described previously in dogs anesthetized with 1.5% halothane but not given thiopental. The total volume of distribution of the highly lipophilic drug thiopental was more than 60% larger than that of antipyrine, 53 versus 33 liters, respectively. Nonetheless, the initial distribution kinetics of the two drugs, including the pulmonary tissue volume and the volume of the nondistributive pathway as well as the clearance to it, were nearly identical. As a result, the fraction of cardiac output involved in distribution of the two drugs to peripheral tissues was similarly identical, although the distribution of cardiac output between clearance to the rapidly equilibrating tissues and clearance to the slowly equilibrating tissues differed slightly. This study validates the assumption that antipyrine is a useful surrogate for lipophilic drugs in pharmacokinetic studies in which physiologic stability is desirable to meet the assumption of system stationarity.
Footnotes
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↵1 Current address: Department of Anesthesiology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box B-113, Denver, CO 80262.
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This study was supported in part by National Institutes of Health Grants GM43776 and GM47502.
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DOI: 10.1124/jpet.102.034611
- Abbreviations:
- ICG
- indocyanine green
- HPLC
- high-performance liquid chromatography
- MTT
- mean transit time
- VC
- central volume
- VT-P
- pulmonary tissue volume
- VND
- nondistributive peripheral pathway volume
- CLND
- clearance to the nondistributive peripheral pathway
- VND-F
- fast nondistributive peripheral pathway volume
- CLND-F
- clearance to the fast nondistributive peripheral pathway
- VND-S
- slow nondistributive peripheral pathway volume
- CLND-S
- clearance to the slow nondistributive peripheral pathway
- VT-F
- rapidly (fast) equilibrating tissue compartment volume
- CLT-F
- clearance to the rapidly (fast) equilibrating peripheral tissue compartment
- VT-S
- slowly equilibrating tissue compartment volume
- CLT-S
- clearance to the slowly equilibrating peripheral tissue compartment
- CLE
- elimination clearance
- VSS
- total (steady-state) volume of distribution
- CLtot
- (ΣCL), total (sum) of all (peripheral and elimination) clearances
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- Received February 14, 2002.
- Accepted April 24, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
