Bactrian (“Double Hump”) Acetaminophen Pharmacokinetics: A Case Series and Review of the Literature

Abstract

After acute ingestion, acetaminophen (APAP) is generally absorbed within 4 h and the APAP concentration ([APAP]) slowly decreases with a predictable half-life. Alterations in these pharmacokinetic principles have been rarely reported. We report here three cases of an unusual double hump, or Bactrian, pattern of [APAP]. We review the literature to describe the case characteristics of these rare cases. A 38-year-old woman ingested 2 g hydrocodone/65 g acetaminophen. Her [APAP] peaked at 289 mcg/mL (8 h), decreased to 167 mcg/mL (31 h), then increased to 240 mcg/mL (39 h). She developed liver injury (peak AST 1603 IU/L; INR1.6). A 25-year-old man ingested 2 g diphenhydramine/26 g APAP. His [APAP] peaked at 211 mcg/mL (15 h), decreased to 185 mcg/mL (20 h), and increased again to 313 mcg/mL (37 h). He developed liver injury (peak AST 1153; INR 2.1). A 16-year-old boy ingested 5 g diphenhydramine and 100 g APAP. His [APAP] peaked at 470 mcg/mL (25 h), decreased to 313 mcg/mL (36 h), then increased to 354 mcg/mL (42 h). He developed liver injury (peak AST 8,686 IU/L; peak INR 5.9). We report three cases of Bactrian ("double hump") pharmacokinetics after massive APAP overdoses. Cases with double hump pharmacokinetics may be associated with large ingestions (26-100 g APAP) and are often coingested with antimuscarinics or opioids. Several factors may contribute to these altered kinetics including the insolubility of acetaminophen, APAP-induced delays in gastric emptying, opioid or antimuscarinic effects, or enterohepatic circulation. Patients with double hump APAP concentrations may be at risk for liver injury, with AST elevations and peaks occurring later than what is typical for acute APAP overdoses.

Outcomes from massive paracetamol overdose: a retrospective observational study

“…It is known that NAPQI generation rises with increasing paracetamol dose, and also that hepatic injury prolongs paracetamol half‐life. Furthermore, there are several case reports, and one observational study, of patients developing hepatotoxicity despite receiving acetylcysteine within 8 h of reported overdose .…”

“…In particular, it is not clear whether the modelling assumptions underlying the initial acetylcysteine dose calculations hold true with very large overdoses, and whether therapy could be better tailored to individual cases in these situations . Several case reports, and one recent observational study, highlight adverse outcomes in patients with massive paracetamol overdoses despite early acetylcysteine treatment . Such patients have higher cysteine and mercapturate to glucuronide conjugate ratios, implying increased proportions of paracetamol undergoing conversion to NAPQI and consistent with the need for supplemental acetylcysteine beyond that suggested by the original models .…”

Intravenous acetylcysteine for the treatment of acetaminophen overdose

“…Other patients do poorly, developing hepatic failure, prolonged hospital stays, transfers to transplantation centers and death [26,[33][34][35]. Patients with these adverse outcomes have complicated presentations, with a number of red flags: massive overdoses, acetaminophen combination or modified-release formulations, high PAC ‡ 300 mg/l ( ‡ 1986 µmol/l) line and/or persistently elevated PACs, some with double peaks [26,30,31,34,35]. Conceivably, molar equivalences of acetylcysteine to acetaminophen are not being met by extended infusions.…”

ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose

“…Since approval of IV NAC in the USA, several reported cases have documented rising hepatic aminotransferase concentrations or persistent serum APAP concentrations despite 21 h of treatment [6][7][8]. With a short elimination half-life after therapeutic dosing, APAP is typically eliminated within 21 h after an acute overdose.…”

“…However, hepatic injury can slow acetaminophen metabolism and prolong its apparent half-life [9]. In addition, altered absorption following massive ingestion [6] or coingestants that slow gastrointestinal motility [7] can result in persistently elevated acetaminophen concentrations.…”