title: Mechanism-based pharmacokinetic-pharmacodynamic modeling of the respiratory-depressant effect of buprenorphine and fentanyl in rats.
abstract: The purpose of this investigation was to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model to predict the time course of respiratory depression following administration of opioids in rats. The proposed model is based on receptor theory and aims at the separate characterization of biophase distribution and receptor association/dissociation kinetics as determinants of hysteresis between plasma concentration and effect. Individual concentration time courses of buprenorphine and fentanyl were determined in conjunction with continuous monitoring of respiratory depression. Buprenorphine and fentanyl were administered intravenously in various doses. For buprenorphine hysteresis was best described by a combined biophase distribution-receptor association/dissociation model with a linear transducer function. The values of the parameter estimates of the rate constants for biophase distribution (k(eo)), receptor association (k(on)), and dissociation (k(off)) were 0.0348 min(-1) [95% confidence interval (CI), 0.0193-0.0503 min(-1)], 0.57 ml/ng/min (95% CI, 0.38-0.76 ml/ng/min), and 0.0903 min(-1) (95% CI, 0.035-0.196 min(-1)), respectively. The values of the equilibrium dissociation constant and intrinsic activity were 0.16 ng/ml and 0.48 (95% CI, 0.45-0.51), respectively. The value of the K(d) is close to reported estimates of receptor affinity in vitro confirming the validity of the mechanism-based PK/PD model. For fentanyl, unrealistically high estimates of the rate constants for receptor association and dissociation were obtained, indicating that hysteresis is caused solely by biophase distribution kinetics. This is consistent with fentanyl's fast receptor association/dissociation kinetics in vitro. As a result, the mechanism-based PK/PD model of fentanyl could be reduced to a biophase distribution model with fractional sigmoid E(max) pharmacodynamic model.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Yassen
authors.forename: Jingmin
authors.initials: J
authors.lastname: Kan
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Ernst
authors.initials: E
authors.lastname: Suidgeest
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000818:Animals; D002047:Buprenorphine / Q000493:pharmacokinetics / Q000494:pharmacology*; D005283:Fentanyl / Q000493:pharmacokinetics / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects*
chemical_list: D009294:Narcotics; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002047:Buprenorphine; D005283:Fentanyl