Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

Abstract

Acetaminophen (paracetamol) is a widely used drug that causes adverse drug events that are often dose-dependent and related to plasma drug concentrations. Acetaminophen metabolism strongly depends on UGT1A enzymes. We aimed to investigate putative factors influencing acetaminophen pharmacokinetics. We analyzed acetaminophen pharmacokinetics after intravenous administration in 186 individuals, and we determined the effect of sex; body mass index (BMI); previous and concomitant therapy with UGT1A substrates, inhibitors, and inducers; as well as common variations in the genes coding for UGT1A1, UGT1A6, and UGT1A9. We identified sex and UGT1A6 genetic variants as major factors influencing acetaminophen pharmacokinetics, with women showing lower clearance (p < 0.001) and higher area under the plasma drug concentration-time curve (AUC) values than men (p < 0.001). UGT1A6 genetic variants were related to decreased acetaminophen biodisposition. Individuals who were homozygous or double-heterozygous for variant UGT1A6 alleles showed a 22.5% increase in t1/2 values and a 22.8 increase in drug exposure (p < 0.001, and 0.006, respectively) after correction by sex. The effect is related to the UGT1A6*2 and UGT1A6*4 variant alleles, whereas no effect of UGT1A6*3 and UGT1A9*3 alleles, BMI, or drug–drug interaction was identified in this study. We conclude that sex and UGT1A6 variants determine acetaminophen pharmacokinetics, thus providing evidence to eventually developing pharmacogenomics procedures and recommendations for acetaminophen use.

Icaritin exhibits potential drug–drug interactions through the inhibition of human UDP‐glucuronosyltransferase in vitro

“…Icaritin has a strong inhibitory effect on UGT1A9 (K i = 0.306 and 1.431 μM), indicating a strong binding effect of icaritin on the active site of UGT1A9 and inhibition of UGT1A9 with continued binding to icaritin. UGT1A9 is particularly involved in the glucuronidation of acetaminophen (Cerezo‐Arias et al., 2022). Co‐administration of acetaminophen with icaritin could enhance acetaminophen toxicity and potentially lead to fatal acute failure (Barker et al., 1977; Liu et al., 2011; Ridruejo et al., 2007; Weise et al., 2009).…”