Disposition of Acetaminophen at 4, 6, and 8 g/day for 3 Days in Healthy Young Adults

Abstract

The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single-dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher, strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose-dependent differences were detected in fCL of thiol metabolites formed via cytochrome P4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose-dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time-dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short-term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults.

Paracetamol for intravenous use in medium- and intensive care patients: pharmacokinetics and tolerance

“…Paracetamol is, when used in therapeutic dosages, generally well tolerated. However, in overdosage, it can cause severe hepatic necrosis [1,2]. In the ICU/MCU, paracetamol is mostly administered as a rectal formulation.…”

Quantification of acetaminophen and two of its metabolites in human plasma by ultra-high performance liquid chromatography–low and high resolution tandem mass spectrometry

“…For these reasons, in addition to the multi-components quantification capabilities and sensitivity issues, LC-MS/MS methods have been introduced recently for the measurement of APAP in human plasma [14][15][16][17][18][19][20]. As expected, overall better sensitivities than traditional LC-UV platforms [21][22][23] were obtained. Only one LC-MS/MS method reported the quantification of APAP with its glucuronide conjugate [14].…”

“…Jensen et al developed a LC-UV method for the simultaneous analysis of APAP, APAP-GLUC and APAP-SULF (LLOQ of 180 ng/mL, 1000 ng/mL and 700 ng/mL, respectively) in human plasma [21]. Other LC-UV methods were proposed for the quantification of APAP metabolites such as APAP-CYS in human plasma (starting from 500 or 200 L samples) [23] or serum (starting from 100 L samples) [22], but the sensitivity of the assays did not allow following the time-course of normal doses in a pharmacokinetic study. For the latter, APAP-CYS was not detected in human plasma for a normal dose (800 mg to 1 g of APAP ingested).…”

Proteomic Study of Hepatic Nuclear Extracts in an Adaptive Acetaminophen Tolerance Model

“…At therapeutic doses, it is an effective analgesic and antipyretic; however, when consumed in large quantities due to accidental or deliberate overdose, APAP is the leading cause of drug-induced acute liver failure [1]. As reviewed by Gelotte et al [2], approximately 90% of APAP is metabolized by two rate-limiting factors. The metabolism of both glucuronidation via uridine 5′-diphospho-glucuronosyltransferase (isoform UGT1A6) and sulfotransferase isoforms (SULT1A1 and 1A3) are based upon the availability of their respective inorganic forms and enzymatic transferase activities.…”

“…The primary cytochrome involved in APAP metabolism, CYP2E1, results in the formation of a highly reactive and toxic intermediate N-acetyl-p-benzo-quinone imine (NAPQI) that is subsequently metabolized to glutathione by glutathione-S-transferases. Thiol metabolites of glutathione production include cysteine, mercapturate, methylthioacetaminophen, and methyanesulfinylacetaminophen [2] which are excreted thru the bile or urinary system. In conditions of APAP overdose and oxidative stress, the primary metabolic pathway becomes saturated.…”