Role of glutathione turnover in drug sulfation: differential effects of diethylmaleate and buthionine sulfoximine on the pharmacokinetics of acetaminophen in the rat.

The purpose of this investigation was to examine the role of altered glutathione turnover in regulating sulfation. After diethylmaleate (3.9 mmol/kg i.p.) or buthionine sulfoximine (6 mmol/kg i.p.) injection, rats received an i.v. dose (30 or 150 mg/kg) of acetaminophen. Diethylmaleate pretreatment decreased the total clearance and increased the half-life of acetaminophen. The fraction of the dose recovered in the urine as acetaminophen sulfate and the partial metabolic clearance to acetaminophen sulfate were substantially diminished by diethylmaleate. Conversely, buthionine sulfoximine pretreatment increased the total clearance of acetaminophen and increased the partial metabolic clearance to acetaminophen sulfate. Diethylmaleate produces a prompt increase in glutathione turnover. This more rapidly uses available cysteine, the rate-limiting precursor of glutathione (and probably inorganic sulfate), thus limiting the availability of inorganic sulfate for sulfate conjugation. Importantly, diethylmaleate decreased the total clearance of acetaminophen and the partial clearance to acetaminophen sulfate at a dose of acetaminophen that does not produce complete sulfate depletion. This indicates that diethylmaleate may inhibit sulfation by mechanisms in addition to limiting sulfate availability. Buthionine sulfoximine selectively inhibits gamma-glutamylcysteine synthetase, thereby preventing cysteine utilization for glutathione resynthesis. Cysteine presumably becomes more available for oxidation to inorganic sulfate. These data suggest that glutathione is not normally converted to cysteine for further oxidation to sulfate when the latter endogenous ion is depleted.