title: Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose.
abstract: Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p < 0.001). CVVHDF failed to remove detectable amounts of APAP-CYS in any of the nine subjects studied. Sixty-eight percent of 557 urine samples from 168 subjects contained no detectable APAP-CYS, despite levels in serum up to 16.99 μM. Terminal elimination half-life of serum APAP-CYS was prolonged in patients with renal failure for reasons unrelated to renal urinary adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back-extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP-CYS, suggesting approximate APAP-protein adduct molecular weights ≥ 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal adduct production and protein shedding into urine rather than elimination of serum adducts.
authors.affiliation: Department of Medical Toxicology, Banner Good Samaritan Medical Center; Department of Medicine, and Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA, steven.curry@bannerhealth.com.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Curry
authors.forename: Angela
authors.initials: A
authors.lastname: Padilla-Jones
authors.forename: Ayrn D
authors.initials: AD
authors.lastname: O'Connor
authors.forename: Anne-Michelle
authors.initials: AM
authors.lastname: Ruha
authors.forename: Dale S
authors.initials: DS
authors.lastname: Bikin
authors.forename: Diana G
authors.initials: DG
authors.lastname: Wilkins
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Rollins
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Slawson
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gerkin
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000506:poisoning* / Q000652:urine; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics* / Q000506:poisoning* / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D015331:Cohort Studies; D003545:Cysteine / Q000031:analogs & derivatives / Q000652:urine; D062787:Drug Overdose / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D005260:Female; D006207:Half-Life; D017583:Hemodiafiltration / Q000379:methods*; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011506:Proteins / Q000493:pharmacokinetics*; D012079:Renal Circulation; D051437:Renal Insufficiency / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D053719:Tandem Mass Spectrometry
chemical_list: D018712:Analgesics, Non-Narcotic; D011506:Proteins; D000082:Acetaminophen; C069744:acetaminophen cysteine; D003545:Cysteine