Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers

• Published in: Clinical pharmacology and therapeutics 2002-08, Vol.72 (2), p.151-162
• Main Authors: Lötsch, Jörn, Skarke, Carsten, Schmidt, Helmut, Liefhold, Jürgen, Geisslinger, Gerd
• Format: Article
• Language: English
• Subjects: Adult; Analgesics; Analgesics, Opioid - pharmacokinetics; Biological and medical sciences; Female; Humans; Injections, Intravenous; Male; Medical sciences; Models, Statistical; Morphine - administration & dosage; Morphine - blood; Morphine - pharmacokinetics; Morphine Derivatives - administration & dosage; Morphine Derivatives - blood; Morphine Derivatives - pharmacokinetics; Narcotics - administration & dosage; Narcotics - blood; Narcotics - pharmacokinetics; Neuropharmacology; Pharmacology. Drug treatments; Reference Values; Time Factors
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2002.126172

Objective This investigation focused on the development of a predictive model of morphine, including morphine‐6‐glucuronide (M6G) for healthy young volunteers after morphine administration. Methods Population compartmental pharmacokinetic modeling with NONMEM was applied to the plasma concentration‐time data of morphine and M6G obtained from 8 healthy volunteers (4 men and 4 women; age range, 23 to 30 years) after intravenous bolus injection of 5.64 mg morphine base (7.5 mg morphine sulfate) and of 1 mg deuterium‐labeled M6G. Results Two models were identified that described the plasma concentration versus time courses of morphine and M6G after administration of morphine. The model consisted of a standard 3‐compartment model for morphine and a standard 2‐compartment model for M6G, with input into and output from the central compartments. The formation of M6G from morphine was modeled as a fraction of morphine clearance of about 14%, which accounted forthe formation of M6G, and a delay of the appearance of M6G in plasma modeled as afirst‐order process, with a mean metabolic transit time of 17.2 minutes. An alternative model assigned the formation of M6G among the first peripheral compartment of morphine andthe central compartment of M6G. Therefore the alternative 3‐compartment model of morphinehad the input into the central compartment and renal excretory elimination from the central compartment, but the metabolic clearance of morphine started from the first peripheralcompartment. M6G was again modeled with a standard 2‐compartment model. Both models predicted morphine and M6G plasma concentrations available from an independent study with acceptable accuracy and without bias. Conclusions Two models are provided that can predict plasma concentrations of morphine and M6G with acceptable accuracy in healthy young volunteers. Clinical Pharmacology & Therapeutics (2002) 72, 151–162; doi: 10.1067/mcp.2002.126172