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Stereoselective clearance and distribution of intravenous propranolol
Author(s) -
Olanoff Lawrence S,
Walle Thomas,
Walle U Kristina,
Cowart T Douglas,
Gaffney Thomas E
Publication year - 1984
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1984.107
Subject(s) - propranolol , chemistry , volume of distribution , stereoselectivity , pharmacokinetics , enantiomer , pharmacology , distribution (mathematics) , endocrinology , biochemistry , medicine , stereochemistry , mathematical analysis , mathematics , catalysis
Our objective was to determine the kinetics of (+)‐ and (–)‐propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium‐labeled (+)‐propranolol and unlabeled (–)‐propranolol. Plasma concentrations of (+)‐ and (–)‐propranolol as measured by gas chromatography‐mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cl s ) [(+)‐propranolol, 1.21 ± 0.15 l/min; (–)‐propranolol, 1.03 ± 0.12 l/min; P < 0.01] and apparent volume of distribution (Vd) [(+)‐propranolol, 4.82 ± 0.34 l/kg; (‐)‐propranolol, 4.08 ± 0.33 l/kg; P < 0.001], but no difference in distribution or elimination t½s (t½β 3.5 hr). The higher Cl s of (+)‐propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)‐propranolol is mainly related to its lower plasma binding [(–)‐propranolol, 20.3 ± 0.8% unbound; (–)‐propranolol, 17.6 ± 0.7% unbound; P < 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites. Clinical Pharmacology and Therapeutics (1984) 35 , 755–761; doi: 10.1038/clpt.1984.107