title: Animal-to-human extrapolation of the pharmacokinetic and pharmacodynamic properties of buprenorphine.
abstract: OBJECTIVE
  This investigation describes the interspecies scaling of the pharmacokinetics and pharmacodynamics of buprenorphine.
  
  
  METHODS
  Data on the time course of the antinociceptive and respiratory depressant effects of buprenorphine in rats and in humans were simultaneously analysed on the basis of a mechanism-based pharmacokinetic-pharmacodynamic model.
  
  
  RESULTS
  An allometric three-compartment pharmacokinetic model described the time course of the concentration in plasma. The value of the allometric coefficient for clearance was 35.2 mL/min (relative standard error [RSE] = 5.6%) and the value of the allometric exponent was 0.76 (RSE 5.61%). A combined biophase distribution-receptor association/dissociation model with a linear transduction function described hysteresis between plasma concentration and effect. The values of the drug-specific pharmacodynamic parameters were identical in rats and in humans. For the respiratory depressant effect, the values of the second-order rate constant of receptor association (k(on)) and the first-order rate constant of receptor dissociation (k(off)) were 0.23 mL/ng/min (RSE = 15.8%) and 0.014 min(-1) (RSE = 27.7%), respectively, and the value of the equilibrium dissociation constant (K(diss)) was 0.13 nmol/L. The value of the intrinsic activity alpha was 0.52 (RSE = 3.4%). For the antinociceptive effect, the values of the k(on) and k(off) were 0.015 mL/ng/min (RSE = 18.3%) and 0.053 min(-1) (RSE = 23.1%), respectively. The value of the K(diss) was 7.5 nmol/L. An allometric equation described the scaling of the system-specific parameter, the first-order distribution rate constant (k(e0)). The value of the allometric coefficient for the k(e0) was 0.0303 min(-1) (RSE = 11.3%) and the value of the exponent was -0.28 (RSE = 9.6%).
  
  
  CONCLUSIONS
  The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid mu receptor subtypes involved in the antinociceptive and respiratory depressant effects.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorleaus Laboratories, Leiden, The Netherlands.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Yassen
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Jingmin
authors.initials: J
authors.lastname: Kan
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000818:Animals; D002047:Buprenorphine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D006801:Humans; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results; D012131:Respiratory Insufficiency / Q000139:chemically induced
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine