Influence of Cardiac Output on Dexmedetomidine Pharmacokinetics

Dexmedetomidine, a highly selective α2‐adrenoceptor agonist, reduces the requirements for anesthetic, analgesic, sedative, and hypnotic drugs. Dexmedetomidine pharmacokinetics were characterized in healthy subjects after intravenous administration by means of a computer‐controlled infusion pump. A s...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2000-04, Vol.89 (4), p.519-527
Main Authors: Dutta, Sandeep, Lal, Ritu, Karol, Michael D., Cohen, Theodora, Ebert, Thomas
Format: Article
Language:English
Subjects:
Adolescent
Adrenergic alpha-Agonists - pharmacokinetics
Adult
Biological and medical sciences
Cardiac Output - physiology
Catecholaminergic system
Dexmedetomidine - pharmacokinetics
Humans
Male
Medical sciences
Middle Aged
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
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Summary:Dexmedetomidine, a highly selective α2‐adrenoceptor agonist, reduces the requirements for anesthetic, analgesic, sedative, and hypnotic drugs. Dexmedetomidine pharmacokinetics were characterized in healthy subjects after intravenous administration by means of a computer‐controlled infusion pump. A series of seven stepwise increasing pseudo‐steady‐state plasma concentrations were targeted. The influence of cardiac output on the pharmacokinetics was investigated by use of a compartmental modeling approach in which the elimination clearance was characterized as being either cardiac output independent or dependent. At dexmedetomidine concentrations of 0, 0.6, and 1.2 ng/mL, mean (SD) estimated cardiac outputs were 5.6 (0.85), 5.1 (0.67), and 4.5 (0.83) L/min, and mean (SD) clearances were 40 (10), 38 (9.0), and 35 (8.5) L/h, respectively. Dexmedetomidine VSS and elimination half‐life were 72 (19) L and 1.9 (0.62) h, respectively. The approximately 3 to 19% decrease in cardiac output observed within the anticipated therapeutic range of 0.3 to 1.2 ng/mL was similar to that observed for clonidine. The decrease in cardiac output with increasing plasma concentrations of dexmedetomidine resulted in a corresponding decrease in drug elimination clearance of ≤12% within the therapeutic range; however, this decrease in dexmedetomidine clearance is likely not clinically relevant. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 519–527, 2000
ISSN:0022-3549
1520-6017
DOI:10.1002/(SICI)1520-6017(200004)89:4<519::AID-JPS9>3.0.CO;2-U