title: Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts.
abstract: BACKGROUND
  In several countries medical prescription of diacetylmorphine is currently being evaluated as a treatment option for heavily dependent narcotic addicts. Because of damaged veins, many patients administer diacetylmorphine intramuscularly or orally. Therefore we characterized the pharmacokinetics of intramuscular and oral diacetylmorphine in the high dose range usually required in narcotic addicts.
  
  
  METHODS
  Three intramuscular doses, 3 oral doses, and 1 intravenous dose of diacetylmorphine and oral and intravenous test doses of deuterium-labeled morphine (morphine-N-methyl-d3 [morphine-d3]) were administered to 8 heroin-addicted patients. Arterial plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 were measured by liquid chromatography-mass spectrometry.
  
  
  RESULTS
  Intramuscularly administered diacetylmorphine (</=200-250 mg) exhibited linear diacetylmorphine, monoacetylmorphine, and morphine kinetics and resulted in sustained diacetylmorphine exposures (bioavailability, 380% +/- 157% [mean +/- SD]) and in lower and delayed peak monoacetylmorphine and morphine concentrations as compared with intravenous administration. Oral diacetylmorphine (</=600 mg) yielded negligible systemic diacetylmorphine and monoacetylmorphine exposures but was associated with linear kinetics and high bioavailabilities for morphine (67% +/- 19%), morphine-3-glucuronide (205% +/- 52%), and morphine-6-glucuronide (180% +/- 61%). In addition, oral diacetylmorphine was absorbed more rapidly and to a greater extent than a concomitant test dose of morphine-d3.
  
  
  CONCLUSIONS
  On the basis of the linear pharmacokinetics, the high bioavailability of intramuscular diacetylmorphine, and the rapid and extended morphine absorption from oral diacetylmorphine, the intramuscular and oral routes can be recommended as safe and feasible alternatives to the intravenous route for medical prescription of diacetylmorphine.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zürich, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Girardin
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Rentsch
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Schwab
authors.forename: Marco
authors.initials: M
authors.lastname: Maggiorini
authors.forename: Christiane
authors.initials: C
authors.lastname: Pauli-Magnus
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Karin
authors.initials: K
authors.lastname: Fattinger
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D005260:Female; D006207:Half-Life; D003932:Heroin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006556:Heroin Dependence / Q000378:metabolism*; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009294:Narcotics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D009294:Narcotics; D003932:Heroin