Nitric oxide induced sinusoidal relaxation after a propranolol priming dose in the perfused rat liver reduces propranolol availability on subsequent dosing

Liu, Xin, Zou, Yuhong, Khlentzos, Alexander M., Yang, Yan, Nikolovski, Julijana, Weiss, Michael and Roberts, Michael S. (2010) Nitric oxide induced sinusoidal relaxation after a propranolol priming dose in the perfused rat liver reduces propranolol availability on subsequent dosing. Clinical and Experimental Pharmacology and Physiology, 37 10: 1028-1033. doi:10.1111/j.1440-1681.2010.05434.x


Author Liu, Xin
Zou, Yuhong
Khlentzos, Alexander M.
Yang, Yan
Nikolovski, Julijana
Weiss, Michael
Roberts, Michael S.
Title Nitric oxide induced sinusoidal relaxation after a propranolol priming dose in the perfused rat liver reduces propranolol availability on subsequent dosing
Journal name Clinical and Experimental Pharmacology and Physiology   Check publisher's open access policy
ISSN 0305-1870
Publication date 2010-10
Sub-type Article (original research)
DOI 10.1111/j.1440-1681.2010.05434.x
Volume 37
Issue 10
Start page 1028
End page 1033
Total pages 6
Place of publication Richmond, VIC, Australia
Publisher Wiley-Blackwell Publishing Asia
Collection year 2011
Language eng
Formatted abstract
1. The present study sought to explain the mechanism leading to reduced availability of propranolol when given after a priming dose in the single-pass perfused rat liver.

2. Extracellular sucrose space (as a measure of sinusoidal relaxation) in perfused rat liver before and after propranolol or propranolol and NG-nitro-l-arginine methyl ester (l-NAME; nitric oxide (NO) synthase inhibitor) treatment were examined. The results showed that propranolol induces sinusoidal relaxation in the perfused liver and this effect could be abolished by NO synthase inhibitor l-NAME.

3. Two bolus injections of propranolol were given to the isolated perfused rat liver and outflow concentration-time profiles of intact propranolol were determined. A two-phase physiologically based organ pharmacokinetic model was applied to estimate hepatocellular influx, efflux, binding, ion-trapping and metabolic elimination pharmacokinetic parameters for propranolol. The recovery of propranolol in the second injection was approximately 54% of that in the first injection. The permeability-surface area product, the binding and the intrinsic clearance all increased significantly after prior exposure of the rat liver to the first bolus of propranolol (P < 0.05).

4. Based on the findings of the present study, we propose that the most likely explanation for the reduced availability of a second propranolol dose (after administration of a priming dose) in the perfused liver is a consequence of the NO-mediated sinusoidal relaxation effect of propranolol, arising from the priming dose. This observation supports the view that the pharmacokinetics of some drugs might be altered by the pharmacodynamic effects of the same drug given earlier in the perfused liver.
Keyword nitric oxide
oxygen consumption
perfused rat liver
propranolol
sinusoidal relaxation
Hepatic Elimination
Disposition Kinetics
Cytoplasmic-binding
Drug
pharmacokinetics
Clearance
flow
Taurocholate
Inhibition
Exchange
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 23 JUL 2010

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
 
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Created: Tue, 16 Nov 2010, 10:25:53 EST by Dr Xin Liu on behalf of Medicine - Princess Alexandra Hospital