QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.115972v1 321/2/598    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yassen, A. Articles by Danhof, M. Search for Related Content PubMed PubMed Citation Articles by Yassen, A. Articles by Danhof, M.

NEUROPHARMACOLOGY

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, Leiden, The Netherlands (A.Y., J.K., E.S., M.D.); and Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (E.O., A.D.)

The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32–1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK-PD relationship best. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.

Address correspondence to: Meindert Danhof, Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: m.danhof{at}lacdr.leidenuniv.nl