Document Detail

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers.
MedLine Citation:
PMID:  16732095     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers. METHODS: Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. RESULTS: A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1)). CONCLUSION: This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.
Ashraf Yassen; Erik Olofsen; Raymonda Romberg; Elise Sarton; Meindert Danhof; Albert Dahan
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anesthesiology     Volume:  104     ISSN:  0003-3022     ISO Abbreviation:  Anesthesiology     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-29     Completed Date:  2006-06-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1232-42     Citation Subset:  AIM; IM    
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, The Netherlands.
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MeSH Terms
Analgesics, Opioid / pharmacokinetics,  pharmacology*
Buprenorphine / pharmacokinetics*,  pharmacology*
Double-Blind Method
Models, Biological
Reg. No./Substance:
0/Analgesics, Opioid; 52485-79-7/Buprenorphine

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