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.
OBJECTIVE
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 < or =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.
Hedmer
Maria
M
Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University Hospital, 221 85 Lund, Sweden. maria.hedmer@med.lu.se
Höglund
Peter
P
Cavallin-Ståhl
Eva
E
Albin
Maria
M
Jönsson
Bo A G
BA
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine*; D015415:Biomarkers; D001943:Breast Neoplasms; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine*; D005260:Female; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018570:Risk Assessment
D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D003520:Cyclophosphamide