Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status

Abstract

SUMMARYAim: To study the pharmacokinetic and metabolism profiles of a single dose of acetaminophen in patients with cirrhosis. Methods: Oral acetaminophen (1000 mg) was administered to seven healthy subjects and 14 patients with cirrhosis (nine Child-Pugh A or B and five Child-Pugh C grade), being five without and nine with oesophageal varices. Plasma levels of acetaminophen and its metabolites were determined by HPLC. Results: Patients showed a higher mean area under the curve concentration-time (67.4 ± 22.4 mg h/L vs. 38.8 ± 4.3 mg h/L; P ¼ 0.01), a lower clearance (166.7 ± 85.0 mL/min vs. 367.8 ± 62.5 mL/min; P ¼ 0.01) and higher elimination half-life (3.8 ± 1.1 h vs. 2.0 ± 0.4 h; P ¼ 0.01) of acetaminophen than healthy volunteers. The appearance in blood and the urinary excretion of metabolites in patients did not differ from healthy subjects. Absorption profile was faster in patients. Patients with lower mean and systolic arterial pressure had lower AUC of acetaminophen, independently of liver dysfunction stage. Conclusions: Patients with cirrhosis had a higher AUC and lower clearance of acetaminophen. Acetaminophen attained earlier therapeutic concentrations in patients with oesophageal varices. Mean and systolic arterial pressures were significantly associated with AUC suggesting the importance of the haemodynamic function on the pharmacokinetics of acetaminophen in patients with cirrhosis.

Acute Effects of Dipyrone on Renal Function in Patients with Cirrhosis: A Randomized Controlled Trial

“…However, we have previously shown that acetaminophen is safe in patients with cirrhosis, but when compared with healthy volunteers, acetaminophen concentrations reached after a dose of 1000 mg were double [22]. According to this observation, the dose of acetaminophen used in the study, which was the recommended minimum dose (500 mg tid), was effective in controlling mild pain and fever in all patients.…”

Effect of Excipients on Acetaminophen Metabolism and Its Implications for Prevention of Liver Injury

“…Power analysis was based on the following assumptions: we expected approximately five to ten percent of the ingested APAP to undergo reductive metabolism. [16][17][18] Assuming a difference of 50% between groups, a calculated sample size of ten subjects would exceed the number needed to enroll with a power of at least 80%. To allow for attrition, we planned to enroll 15 subjects.…”

Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia in Japanese Patients with Chronic Pain

“…The pharmacokinetics of APAP have been reported in patients with chronic renal failure, 17) portal hypertension, 20) and chronic liver disease. 21,22) In patients with these diseases, the APAP half-life was long compared with that in healthy volunteers.…”