Metabolism of antipyrine and m-xylene in rats after prolonged pretreatment with xylene alone or xylene with ethanol, phenobarbital or 3-methylcholanthrene.

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 (less than or equal to 14%, P less than 0.001), norantipyrine (NORA) (less than or equal to 23%, P less than 0.01) and AP (less than or equal to 53%, P less than 0.01) decreased. 4-Hydroxyantipyrine (4-OHA) was unchanged. 3. Oral dosage of XYL at 800 mg/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 less than 0.01), 3-HMA (11-42%, P less than 0.05) and AP (greater than or equal to 50%, P less than 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 less than 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.