Division of Clinical Pharmacology and Toxicology, University Hospital Basel, 4031, Basel, Switzerland.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Clin Pharmacokinet. 2023 Aug;62(8):1141-1155. doi: 10.1007/s40262-023-01261-3. Epub 2023 Jun 16.
The impact of liver cirrhosis on the activity of UDP-glucuronosyltransferases (UGTs) is currently not well characterized. We investigated the glucuronidation capacity and glucuronide accumulation in patients with liver cirrhosis.
We administered the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, midazolam) to patients with liver cirrhosis (n = 16 Child A, n = 15 Child B, n = 5 Child C) and n = 12 control subjects and obtained pharmacokinetic profiles of substrates and primary metabolites and their glucuronides.
Caffeine and its metabolite paraxanthine were only slightly glucuronidated. The metabolic ratio (AUC/AUC, MR) was not affected for caffeine but decreased by 60% for paraxanthine glucuronide formation in Child C patients. Efavirenz was not glucuronidated whereas 8-hydroxyefavirenz was efficiently glucuronidated. The MR of 8-hydroxyefavirenz-glucuronide formation increased three-fold in Child C patients and was negatively correlated with the glomerular filtration rate. Flurbiprofen and omeprazole were not glucuronidated. 4-Hydroxyflurbiprofen and 5-hydroxyomeprazole were both glucuronidated but the corresponding MRs for glucuronide formation were not affected by liver cirrhosis. Metoprolol, but not α-hydroxymetoprolol, was glucuronidated, and the MR for metoprolol-glucuronide formation dropped by 60% in Child C patients. Both midazolam and its metabolite 1'-hydroxymidazolam underwent glucuronidation, and the corresponding MRs for glucuronide formation dropped by approximately 80% in Child C patients. No relevant glucuronide accumulation occurred in patients with liver cirrhosis.
Detailed analysis revealed that liver cirrhosis may affect the activity of UGTs of the UGT1A and UGT2B subfamilies according to liver function. Clinically significant glucuronide accumulation did not occur in the population investigated.
NCT03337945.
目前，肝硬化对 UDP-葡糖醛酸基转移酶（UGTs）活性的影响尚不清楚。本研究旨在调查肝硬化患者的葡糖醛酸化能力和葡糖醛酸化物的蓄积情况。
我们给 16 例 Child A 期、15 例 Child B 期和 5 例 Child C 期肝硬化患者和 12 例健康对照者服用巴塞尔表型鸡尾酒（咖啡因、依非韦伦、氟比洛芬、奥美拉唑、美托洛尔、咪达唑仑），并获得了底物和初级代谢物及其葡糖醛酸化物的药代动力学特征。
咖啡因及其代谢物 1,7-二甲基黄嘌呤仅轻度葡糖醛酸化。代谢比值（AUC/AUC，MR）对咖啡因无影响，但对 Child C 期患者的 1,7-二甲基黄嘌呤葡糖醛酸化物形成降低 60%。依非韦伦不发生葡糖醛酸化，而 8-羟基依非韦伦则能有效地葡糖醛酸化。Child C 期患者的 8-羟基依非韦伦葡糖醛酸化物形成的 MR 增加了三倍，且与肾小球滤过率呈负相关。氟比洛芬和奥美拉唑不发生葡糖醛酸化。4-羟基氟比洛芬和 5-羟基奥美拉唑均能发生葡糖醛酸化，但葡糖醛酸化物形成的相应 MR 不受肝硬化影响。美托洛尔，但不是 α-羟美托洛尔，能发生葡糖醛酸化，而 Child C 期患者的美托洛尔葡糖醛酸化物形成的 MR 降低了 60%。咪达唑仑及其代谢产物 1'-羟基咪达唑仑均能发生葡糖醛酸化，而 Child C 期患者的相应葡糖醛酸化物形成的 MR 降低了约 80%。肝硬化患者未发生相关的葡糖醛酸化物蓄积。
详细分析显示，根据肝功能，肝硬化可能会影响 UGT1A 和 UGT2B 亚家族的 UGT 活性。在本研究人群中未发生有临床意义的葡糖醛酸化物蓄积。
NCT03337945。
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