Kinetics and metabolism of 1,4-dichlorobenzene in male Wistar rats: no evidence for quinone metabolites

Abstract

The biotransformation and kinetics of 1,4-dichlorobenzene (1,4-DCB) were studied in male Wistar rats at three oral dose levels (10, 50 and 250 mg/kg). The effect of induction of CYP2E1 by isoniazid on the kinetics and biotransformation was determined. Excretion was predominantly via the urine (78–85%) and to a small extent via the faeces (2–5%). The relative contributions of these routes were not dose dependent. Excretion via the bile ranged from less than 5% at the low dose level to 30% at the high dose level. The major biliary metabolite was the glucuronide of 2,5-dichlorophenol (2,5-DCP). The time point at which the plasma concentrations of the parent compound and the metabolites were maximal ( T Cmax) as well as the maximum concentrations ( C max) increased with higher dose level. Induction by isoniazid resulted in a faster urinary elimination, whereas T Cmax and C max were lower for induced rats. In addition, the area under the blood curve (AUC) was smaller and total clearance was higher for induced rats. 1,4-DCB was mainly metabolized to 2,5-DCP (ca. 90%), which was detected in the urine as its sulfate (50–60%), glucuronide (20–30%) and the free form (5–10%). Minor metabolites were the N-acetyl-cysteine- S-dihydro-hydroxy-1, 4-dichlorobenzene and the corresponding dehydrated N-acetyl-cysteine- S-1,4-dichlorobenzene, which comprised ca. 10% of total metabolites. No hydroquinones were observed for the male Wistar rat, not even under conditions of induced oxidative metabolism.