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Abstract
1. The metabolic disposition of antipyrine (AP) and m-xylene (XYL) has been studied in rats pretreated for a prolonged period with XYL, dosed alone or in combination with ethanol, phenobarbital (PB), or 3-methylcholanthrene (MC).
2. XYL inhalation exposure at 300 ppm in air (7 h/day, 4 days/week, for 1 or 4 weeks) did not alter the total 24-h recovery of AP and its major metabolites in urine, but the excretion profile changed compared with controls: 3-hydroxymethylantipyrine (3-HMA) increased (≤14%, P<0.001), norantipyrine (NORA) (≤23%, P<0.01) and AP (≤53%, P<0.01) decreased. 4-Hydroxyantipyrine (4-OHA) was unchanged.
3. Oral dosage of XYL at 800mg/kg per day (5 days/week, for 12 days) altered the metabolic disposition of AP similarly to inhalation.
4. XYL+ethanol did not alter the xylene-type effect on AP metabolism. This was at variance with the changes following XYL + PB and, to a greater extent, XYL + MC pretreatments: 4-OHA increased (53–74%, P<0.01), 3-HMA (11–42%, P<0.05) and AP (≤ 50%, P<0.05) decreased. The effect on NORA was less clear.
5. XYL pretreatment accelerated metabolic disposition of its major urinary metabolite, methylhippuric acid (MHA) and formation of thioethers.
6. Thioether excretion in 24 h urine was enhanced about 10-fold after XYL inhalation and 20-fold after oral administration. Only XYL + PB treatment enhanced further the excretion of xylene-derived thioethers (P<0.05).
7. Drug-metabolizing activity (phase I and II reactions) in liver, lung and kidney showed that the treatments resulted in marked and differential biochemical alterations.
8. In conclusion, m-xylene enhanced the rate of its own metabolism and induced differential changes on urinary AP metabolite profile depending on the pretreatment.