title: The pharmacokinetics of piritramide after prolonged administration to intensive care patients.
abstract: OBJECTIVE
  The purpose of the present study was to determine the pharmacokinetics of the micro-agonist opioid pirinitramide (piritramide) after prolonged administration.
  
  
  METHODS
  Nine patients requiring intensive care therapy and artificial ventilation for several days received piritramide with a median infusion rate of 5 mg h(-1) (range 4.8-10 mg h(-1)) for a median period of 69.9 h (range 49-89 h) for analgesia and sedation. After the end of the infusion, frequent arterial blood samples were withdrawn for 96 h and assayed for piritramide using a gas chromatographic method. Standard compartmental models were fitted to the individual concentration-time courses to characterize the elimination of piritramide after prolonged administration.
  
  
  RESULTS
  The concentration-time course after the end of the infusion was adequately described with a three-compartment model in eight patients and a two-compartment model in one patient (standard two-stage geometric mean and 16-84% quantile: volumes of distribution V1 = 47.9 (26.8-85.8)L, V2 = 402 (241-672)L, V3 = 332 (124-885)L; clearances Cl1 = 66.5 (53.2-83.0)Lh(-1), Cl2 = 215 (125-369)Lh(-1), Cl3 = 18.4 (9.2-36.8) Lh(-1)). Both the steady-state volume of distribution (782 L) and the terminal elimination half-life (17.4 h) were larger than predicted from single bolus pharmacokinetic studies (412.5 L and 10.4 h, respectively), the context-sensitive half-time after more than 72 h of administration was 32% shorter than predicted (285 vs. 420 min).
  
  
  CONCLUSIONS
  Despite increasing terminal elimination half-life and volume of distribution at steady state (increasing drug load for a given plasma concentration), the context-sensitive half-time of piritramide after 3 days of administration is lower than predicted from bolus kinetics, making the drug a suitable candidate for intensive care unit analgesia.
authors.affiliation: Inselspital Berne, Department of Anaesthesia and Intensive Care Medicine, Berne, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Bouillon
authors.forename: P
authors.initials: P
authors.lastname: Groeger
authors.forename: D
authors.initials: D
authors.lastname: Kietzmann
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000927:Anticonvulsants / Q000008:administration & dosage; D002849:Chromatography, Gas / Q000379:methods; D003422:Critical Care / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010672:Phenytoin / Q000008:administration & dosage; D010892:Pirinitramide / Q000097:blood / Q000493:pharmacokinetics*; D012121:Respiration, Artificial / Q000379:methods; D013874:Thiopental / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D000927:Anticonvulsants; D010892:Pirinitramide; D010672:Phenytoin; D013874:Thiopental