Inter‐subject and ethnic differences in paracetamol metabolism.

Abstract

The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

“…We found that Ϸ30% of the 1-g dose was recovered (as any acetaminophen-related compound) in each of the 2 postdose urine collection periods (0-3 h and 3-6 h), this being consistent with the findings of an earlier report (15) where the urinary excretion of acetaminophen, S and G was studied at 1.5-h intervals after a 12 mg/kg dose. Furthermore, we found that, in terms of moles, the combined excretion of S and G typically accounted for Ϸ85% of the total amount of acetaminophen-related compounds recovered in each collection period, this being consistent with the 24-h urinary recoveries from 111 Caucasians given a 1.5-g dose (20). Representative predose and postdose spectra are shown in Fig.…”

“…Acetaminophen is one of the most widely used nonprescription medicines in the world and its toxicology and metabolism have been extensively investigated over many years (14)(15)(16)(17)(18)(19)(20). However, we will show here that, even for this most familiar drug, pharmacometabonomic analysis will yield significantly increased understanding of its metabolic behavior in humans.…”

“…It is also predominantly and relatively rapidly eliminated in the urine (15)(16)(17)(18)(19). Thus, by collecting postdose urine samples we could study the manner of its excretion by each subject, such excretion being known to show considerable intersubject variation (20). Precisely how a particular drug is metabolized and excreted by each individual can have a major influence on its safety and efficacy.…”

“…We then searched for components of intersubject variation in the predose spectra that would correlate with intersubject variation in the postdose data. However, from the outset, prediction of the S/G ratio was of particular interest because this ratio is known to show extensive interindividual variation and is assumed to be indicative of the relative extent to which acetaminophen is metabolized via 2 major phase 2 conjugative processes (O-sulfonation and glucuronidation) that impact on the metabolism of many different drugs (20,21). Additionally, we expected that the S/G ratio would be less susceptible to any sample collection errors than the absolute amounts of metabolites excreted.…”

Impaired absorption of paracetamol in vegetarians.

“…Studies were carried out in 10 healthy male Thai volunteers taking a normal diet and 10 similar subjects who had been taking a vegetarian diet for a mean of 18 …”