A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.
Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.



Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.



A one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration-time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m2increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m2. The clearance of morphine or its metabolites was not found to be correlated with treatment failure.



The influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome. Dutch Trial Register ID: NTR4369.
Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. a.oosten@erasmusmc.nl.
Astrid W
AW
Oosten
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
João A
JA
Abrantes
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Siv
S
Jönsson
Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.|Department of Pediatric Surgery, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
Maja
M
Matic
Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
Ron H N
RHN
van Schaik
Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.
Peter
P
de Bruijn
Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.|Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
Carin C D
CCD
van der Rijt
Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.
Ron H J
RHJ
Mathijssen
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D055104:Infusions, Subcutaneous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000097:blood; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
D000701:Analgesics, Opioid; D014453:Glucuronosyltransferase; D009020:Morphine; D009022:Morphine Derivatives; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027702:Organic Cation Transporter 1; C114462:multidrug resistance-associated protein 3; C035349:morphine-6-glucuronide; C491474:UGT2B7 protein, human; C018108:morphine-3-glucuronide