title: Population Pharmacokinetic Modelling of Morphine, Gabapentin and their Combination in the Rat.
abstract: The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles.
  
  
  
  The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied to describe the pharmacokinetics of the compounds and possible interactions.
  
  
  
  The plasma-concentration-time profiles of morphine and gabapentin were best described using a three- and a one-compartment disposition model respectively. Dose dependencies were found for morphine absorption rate and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation.
  
  
  
  The finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might not have any clinical relevance.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Papathanasiou
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Rasmus Vestergaard
authors.initials: RV
authors.lastname: Juul
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gabel-Jensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark. trine.lund@sund.ku.dk.
authors.forename: Trine Meldgaard
authors.identifier: 0000-0001-8598-2880
authors.initials: TM
authors.lastname: Lund
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004764:Enterohepatic Circulation; D000077206:Gabapentin; D020719:Glucuronides / Q000378:metabolism; D008954:Models, Biological; D009020:Morphine / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D005680:gamma-Aminobutyric Acid / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D020719:Glucuronides; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine
keywords: NONMEM; drug-drug interactions; enterohepatic circulation; gabapentin; morphine