Monitoring paracetamol metabolism after single and repeated administration in pediatric patients with neoplastic diseases.
BACKGROUND
Paracetamol (PCM) is frequently used in pediatric patients with neoplastic disease. It is metabolized mainly by conjugation, but at therapeutic concentrations, a small fraction of the drug undergoes oxidative metabolism via cytochrome P450 forming the hepatotoxic intermediate N-acetyl-p-benzo-quinone-imine (NAPQI) which is usually conjugated with glutathione and excreted as paracetamol mercapturate and paracetamol cysteine.


OBJECTIVE
The aim of this monitoring study was to evaluate PCM metabolism with minimal intervention during routine treatment with single and repeated administration in patients undergoing antineoplastic therapy.


METHODS
A total of 107 urine samples collected 4-12 h after PCM administration from 29 children undergoing antineoplastic treatment, and 10 children without antineoplastic treatment were analyzed for PCM, PCM glucuronide (PCM-G), PCM sulfate (PCM-S), PCM mercapturate (PCM-M) and PCM cysteine (PCM-C).


RESULTS
The median (range) percentages for metabolites in urine were: a) in children with and without chemotherapy after the first administration: PCM: 0 (0-100) and 4 (0-11)%, PCM-G: 55 (0-88) and 51 (18 - 68)%, PCM-S: 30 (0-73) and 32 (22-57)%, PCM-(M+C): 13 (0-52) and 9 (0-24)%, respectively; b) after repeated administration in children with chemotherapy: PCM: 0 (0-51)%, PCM-G: 42 (7-100)%, PCM-S: 28 (0-70)%, PCM-(M+C): 24 (0-66)%.


CONCLUSIONS
The pattern of PCM excretion in children undergoing antineoplastic treatment regimens is highly variable. Repeated administration is associated with a significant increase in the products of oxidative metabolism. This might indicate an increase in metabolism via the hepatotoxic NAPQI.
Koling
S
S
Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Germany. skoling@uni-muenster.de
Hempel
G
G
Lanvers
C
C
Boos
J
J
Würthwein
G
G
D000082:Acetaminophen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D000293:Adolescent; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000031:analogs & derivatives / Q000652:urine; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D007097:Imines; D007223:Infant; D009369:Neoplasms / Q000188:drug therapy; D010084:Oxidation-Reduction
D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C069744:acetaminophen cysteine; C037386:acetaminophen glucuronide; C028473:N-acetyl-4-benzoquinoneimine; D003545:Cysteine; C048094:acetaminophen mercapturate; C045667:acetaminophen sulfate ester