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PhenacetinO-deethylation in extrahepatic tissues of rats

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Summary

PhenacetinO-deethylation is a marker reaction of CYP450 1A2 activity. The drug-metabolizing enzyme is constitutively expressed in liver. In this study, an in vivo rat model for assessment of extrahepatic metabolism was used to investigate phenacetinO-deethylation and the alterations in the disposition of phenacetin due to the loss of liver function. Rats were divided into the model and normal control groups. The model was established according to our previously described method. The concentrations of phenacetin and its major metabolites acetaminophen, glucuronate-acetaminophen and sulfate-acetaminophen in plasma and urine were determined by HPLC. 30 min after intravenous administration of 0.16 % phenacetin 10 mg.kg−1, plasma acetaminophen in the model group was only 3.6 % of that in the control group (0.09±0.04 μg.mL−1 vs 2.49±0.85 μg.mL−1, n=8). 30 min after intragastric injection of 0.4 % phenacetin 30 mg.kg−1, plasma acetaminophen formation was very slight, about 8.6% of plasma phenacetin in the model group (0.74±0.43 μg.mL−1, acetaminophen vs 8.57±8.42 μg.mL−1 phenacetin) and 6.8% in the of plasma phenacetin in the model group (0.74±0.43 μg.mL−1 acetaminophen vs 8.57±8.42 μg.mL−1 phenacetin) and 6.8% in the control group (1.06±0.59 μg.mL−1 acetaminophen vs 15.47±7.21 μg.mL−1 phenacetin, n=8); no significant differences were observed in plasma phenacetin, total acetaminophen and the ratio of acetaminophen to phenacetin between control and model groups. In the urine collected for 3 h after intravenous administration of 0.16% phenacetin 10 mg.kg−1, the total receovery of acetaminophen (as free, glucuronate- and sulfate-acetaminophen) in the model group was 4.6% of that in the control group (4.47±4.27 μg vs 96.63±8.50 μg, n=6), but phenacetin recovery in the model group was 9 times higher than that in the control group (15.03±17.72 μg vs 1.66±0.50 μg). The results indicate that phenacetinO-deethylation in the extrahepatic tissues and the first-pass metabolism of the probe compound seem to be negligible in rats, but the renal excretion of phenacetin, as a compensation, dramatically increases in model rats.

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Authors and Affiliations

  1. Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 200438, Shanghai, China

    Z. F. Cui, P. He, M. Luo, S. Q. Xia & M. C. Wu

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  1. Z. F. Cui
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  2. P. He
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  3. M. Luo
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Cui, Z.F., He, P., Luo, M. et al. PhenacetinO-deethylation in extrahepatic tissues of rats. Eur. J. Drug Metab. Pharmacokinet. 27, 107–111 (2002). https://doi.org/10.1007/BF03190424

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