Cytochrome P450 2C9 mediated metabolism in people with and without cancer.
OBJECTIVE
To compare cytochrome P450 activity in people with and without cancer and examine the relationship between CYP2C9 activity and serum cytokine levels.


METHODS
10 subjects with cancer who were currently receiving treatment and 10 additional subjects without cancer who were matched to the subjects with cancer based on gender and race were enrolled into the study. Serial blood samples were drawn to measure tolbutamide in the plasma before and after oral tolbutamide 500 mg. Total urine excreted was collected from 0 to 12 h following the dose. Tolbutamide and its metabolites were measured in plasma and urine by HPLC. CYP2C9 genotype was determined by PCR and pyrosequencing and cytokine values were determined by ELISA.


RESULTS
The mean apparent oral clearance (cancer, 19.5 +/- 10.5 vs. non-cancer, 15.8 +/- 5.0 ml/min) and the mean urinary metabolic ratio from 0 to 12 h were similar (838 +/- 693 vs. 775 +/- 390). Neither age nor genotype statistically affected the outcomes. Mean interleukin-6 (7.2 +/- 9.4 vs. 1.5 +/- 1.3 pg/ml) and tissue necrosis factor-a (26.2 +/- 71.2 vs. 1.5 +/- 1.3 pg/ml) were 5- to 7-fold higher, respectively, in subjects with cancer. No statistically significant correlation between cytokine values and oral clearance or urinary metabolic ratio was found.


CONCLUSIONS
CYP2C9 activity as measured by apparent oral clearance and urinary metabolic ratio following oral tolbutamide appear similar in people with and without cancer. Serum cytokine values appear higher in patients with cancer, although the differences did not reach statistical significance.
Shord
S S
SS
University of Illinois Medical Center, Clinical Research Center, Chicago, IL, USA. sshord@uic.edu
Cavallari
L H
LH
Viana
M A G
MA
Momary
K
K
Neceskas
J
J
Molokie
R E
RE
Deyo
K
K
Patel
S R
SR
D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D011446:Prospective Studies; D014044:Tolbutamide / Q000493:pharmacokinetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007004:Hypoglycemic Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases