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Validation of urinary excretion of cyclophosphamide as a biomarker of exposure by studying its renal clearance at high and low plasma concentrations in cancer patients

Hedmer, Maria LU ; Höglund, Peter LU ; Cavallin-Ståhl, Eva LU ; Albin, Maria LU and Jönsson, Bo A LU (2008) In International Archives of Occupational and Environmental Health 81(3). p.285-293
Abstract
OBJECTIVES: Cyclophosphamide (CP) is an alkylating agent classified as a human carcinogen. Health care workers handling this drug may be exposed during, e.g., preparation or administration. Cyclophosphamide is readily absorbed by inhalation and by dermal uptake. A biomarker, CP in urine, has frequently been used to assess the occupational exposure to CP, but has not been fully validated. The aim of this study was to investigate if the proportion of the CP dose that is excreted in urine (renal clearance) is constant over different plasma drug concentrations and other pharmacokinetic parameters, e.g., urine flow. METHODS: Pharmacokinetics of CP were studied in 16 breast cancer patients that were treated with postoperative adjuvant... (More)
OBJECTIVES: Cyclophosphamide (CP) is an alkylating agent classified as a human carcinogen. Health care workers handling this drug may be exposed during, e.g., preparation or administration. Cyclophosphamide is readily absorbed by inhalation and by dermal uptake. A biomarker, CP in urine, has frequently been used to assess the occupational exposure to CP, but has not been fully validated. The aim of this study was to investigate if the proportion of the CP dose that is excreted in urine (renal clearance) is constant over different plasma drug concentrations and other pharmacokinetic parameters, e.g., urine flow. METHODS: Pharmacokinetics of CP were studied in 16 breast cancer patients that were treated with postoperative adjuvant chemotherapy including CP. Plasma and urine from the patients were collected at different occasions up to 12 days after the dose. Urine was collected during 4-h periods and blood was sampled at the end of each period. Analysis of CP was performed by liquid chromatography tandem mass spectrometry. The limit of detection for CP in urine and plasma was 0.01 and 0.02 ng/ml, respectively. The precisions of the developed methods were determined to </=8%. RESULTS: The administered doses of CP in absolute amounts ranged between 800 and 2,240 mg. Mean renal clearance of CP was 8.6 (confidence interval 6.5-10.7) ml/min and was not significantly dependent of the plasma drug concentration. However, a significant correlation between renal clearance and urine flow was observed. There was a large inter-individual variation in the plasma and urine concentrations even when the same doses were given. CONCLUSIONS: Cyclophosphamide in urine can be continued to be used as a biomarker to monitor occupational exposure to CP, however the inter-individual variability of excretion of CP in urine, and its dependency on urine flow must be taken into consideration in future applications. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
International Archives of Occupational and Environmental Health
volume
81
issue
3
pages
285 - 293
publisher
Springer
external identifiers
  • wos:000251152100004
  • pmid:17579883
  • scopus:36549020041
ISSN
1432-1246
DOI
10.1007/s00420-007-0211-2
language
English
LU publication?
yes
id
06eb760b-3a4f-49e0-b83e-f651c42e3dc4 (old id 1138320)
date added to LUP
2008-07-28 14:23:38
date last changed
2017-07-09 03:58:19
@article{06eb760b-3a4f-49e0-b83e-f651c42e3dc4,
  abstract     = {OBJECTIVES: Cyclophosphamide (CP) is an alkylating agent classified as a human carcinogen. Health care workers handling this drug may be exposed during, e.g., preparation or administration. Cyclophosphamide is readily absorbed by inhalation and by dermal uptake. A biomarker, CP in urine, has frequently been used to assess the occupational exposure to CP, but has not been fully validated. The aim of this study was to investigate if the proportion of the CP dose that is excreted in urine (renal clearance) is constant over different plasma drug concentrations and other pharmacokinetic parameters, e.g., urine flow. METHODS: Pharmacokinetics of CP were studied in 16 breast cancer patients that were treated with postoperative adjuvant chemotherapy including CP. Plasma and urine from the patients were collected at different occasions up to 12 days after the dose. Urine was collected during 4-h periods and blood was sampled at the end of each period. Analysis of CP was performed by liquid chromatography tandem mass spectrometry. The limit of detection for CP in urine and plasma was 0.01 and 0.02 ng/ml, respectively. The precisions of the developed methods were determined to &lt;/=8%. RESULTS: The administered doses of CP in absolute amounts ranged between 800 and 2,240 mg. Mean renal clearance of CP was 8.6 (confidence interval 6.5-10.7) ml/min and was not significantly dependent of the plasma drug concentration. However, a significant correlation between renal clearance and urine flow was observed. There was a large inter-individual variation in the plasma and urine concentrations even when the same doses were given. CONCLUSIONS: Cyclophosphamide in urine can be continued to be used as a biomarker to monitor occupational exposure to CP, however the inter-individual variability of excretion of CP in urine, and its dependency on urine flow must be taken into consideration in future applications.},
  author       = {Hedmer, Maria and Höglund, Peter and Cavallin-Ståhl, Eva and Albin, Maria and Jönsson, Bo A},
  issn         = {1432-1246},
  language     = {eng},
  number       = {3},
  pages        = {285--293},
  publisher    = {Springer},
  series       = {International Archives of Occupational and Environmental Health},
  title        = {Validation of urinary excretion of cyclophosphamide as a biomarker of exposure by studying its renal clearance at high and low plasma concentrations in cancer patients},
  url          = {http://dx.doi.org/10.1007/s00420-007-0211-2},
  volume       = {81},
  year         = {2008},
}