Acetaminophen elimination half-life in humans is unaffected by short-term consumption of sulfur amino acid-free diet

Abstract

Sulfation and glutathione (GSH) conjugation are important pathways for elimination of acetaminophen (APAP). Previous studies in rodents show that limitation of dietary sulfur amino acids (SAAs) reduces biosynthesis of 3'-phosphoadenosine-5'-phosphosulfate, the precursor for sulfation, and GSH, the precursor for the mercapturatic acid pathway. The amount of SAA needed for the metabolism of two doses of APAP is equivalent to 62% of the recommended dietary allowance (RDA) for SAA in humans. A decrease in the activity of these metabolic pathways could lead to decreased elimination of the reactive metabolite of APAP and possibly affect risk of APAP use. To determine whether intake of a SAA-deficient diet alters APAP metabolism, a pilot clinical study with a double-blind, cross-over design was performed. Subjects received the RDA for SAA for 3 days for equilibration. After admission to the clinical research unit, subjects were given a chemically defined diet with 100 or 0% of the RDA for SAA for 2 days. On day 3, two doses of APAP (15 mg/kg) or placebo were given successively within a 6-h interval. Plasma samples were collected at baseline and hourly for 12 h, and two 6-h urine aliquots were collected during this time course. The data show that SAA limitation 1) did not change the pattern of APAP metabolites in plasma or urine and 2) did not alter APAP pharmacokinetics. Thus, the results show that 2 days of diet completely devoid of SAA have no effect on APAP metabolism or disposition in healthy humans.

Fig. 1.

Plasma concentrations of APAP (A) and APAP metabolites (B–D) after 2 days of an SAA-adequate diet (100% of the RDA) or an SAA-insufficient diet (0% of the RDA). APAP and metabolite concentrations were determined by HPLC. Data are expressed as means ± S.E. for each time point. *, significant at p < 0.05; n = 8.

Fig. 2.

AUC analysis for plasma APAP (A) and metabolites (B) after 2 days of an SAA-adequate diet (100% of the RDA) or an SAA-insufficient diet (0% of the RDA). AUC was calculated by using the APAP metabolite concentrations measured by HPLC analysis (see Fig. 1). *, significant at p < 0.05; n = 8.

Fig. 3.

Effect of sulfur amino acid insufficiency on urinary APAP (A) and APAP metabolite (B–D) recovery. Urine was collected in 6-h intervals after administration of APAP and analyzed by HPLC. Results showed no significant differences caused by consumption of SAA-deficient food for 2 days.

Fig. 4.

Percentages of APAP and APAP metabolites recovered in urine while consuming a diet insufficient (A) or adequate (B) in SAAs. Data are expressed as percentage of cumulative 12-h urinary excretion of APAP metabolites (APAP, APAP-glucuronide, APAP-sulfate, APAP-Cys, APAP-GSH, and APAP-mercapturate) after two doses of APAP (15 mg/kg) given 6 h apart.