UDP-Glucuronosyltransferase 1A1 Is the Principal Enzyme Responsible for Etoposide Glucuronidation in Human Liver and Intestinal Microsomes: Structural Characterization of Phenolic and Alcoholic Glucuronides of Etoposide and Estimation of Enzyme Kinetics

Zhao, Wen; Tallman, Melanie N.; Ali, Shabana Amanda; Smith, Philip C.

doi:10.1124/dmd.106.012732

Cited by 71 publications

(64 citation statements)

References 32 publications

(55 reference statements)

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“…Structure comparisons as well as substrate recognition studies suggest that glucuronidation is occurring on the carboxyl terminus and on the phenolic hydroxyl group. Analyses of the mass spectrum are also consistent with these conclusions (Wen et al, 2007).…”

Section: Discussionsupporting

confidence: 76%

“…Although MS/MS data conclusively identified glucuronidated products for THC-OH and THC-COOH, exact regiochemical assignments are complex because multiple reaction sites exist on these substrates and base product ions in mass spectra represent the loss of glucuronic acid. Additional information regarding regiochemistry of glucuronidation can be determined from fragments derived from the glucuronic acid moiety (Wen et al, 2007). Alcoholic and phenolic glucuronides are known to fragment by specific pathways, yielding ions of m/z 175 and 113 for phenolic glucuronides and of m/z 193, 175, and 113 for alcoholic glucuronides.…”

Section: Mazur Et Almentioning

confidence: 99%

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Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids

et al. 2009

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Section: Discussionsupporting

confidence: 76%

Section: Mazur Et Almentioning

confidence: 99%

Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids

et al. 2009

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“…A possible cause for increased etoposide glucuronide formation would be upregulation of UDPglucuronosyltransferase (UGT) enzyme(s) in the liver. In human liver microsomes, conjugation of etoposide to glucuronic acid is mainly mediated by UGT1A1 (20,21). We therefore evaluated hepatic mRNA levels of Ugt1a1 in WT, Abcc2 -/-, Abcb1a/1b -/-, and Abcb1a/1b;Abcc2 -/-mice.…”

Section: Resultsmentioning

confidence: 99%

P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

Lagas

Fan

Wagenaar

et al. 2010

Clinical Cancer Research

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Purpose: Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.Experimental Design: Abcb1a/1b, Abcc3 -/-, Abcb1a/1b;Abcc2 -/-, and Abcc2;Abcc3 -/-mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.Results: P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2 -/-mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3 -/-mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.Conclusions: P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide. Clin Cancer Res; 16(1); 130-40. ©2010 AACR.

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“…The inhibition of UGT1A1 is particularly important if a drug has a narrow therapeutic index, such as etoposide and irinotecan (Kawato et al, 1991;Wen et al, 2007). It is interesting to note that gefitinib exhibited very weak inhibition against bilirubin glucuronidation in HLMs, although it potently inhibited 4-MU glucuronidation in recombinant UGT1A1.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases

Liu¹,

Ramı́rez²,

House³

et al. 2009

Drug Metab Dispos

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ABSTRACT:We aimed to investigate and compare the effects of erlotinib and gefitinib on UDP-glucuronosyltransferase (UGT) activities and to quantitatively evaluate their drug-drug interaction (DDI) potential due to UGT inhibition. The inhibitory effects of erlotinib and gefitinib on UGTs were determined using high-performance liquid chromatography by measuring the formation rates for 4-methylumbelliferone (4-MU) glucuronide, imipramine N-glucuronide, and bilirubin glucuronides using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of erlotinib and gefitinib. Inhibition kinetic studies were conducted. Area under the curve (AUC) ratios were used to predict the risk of potential DDI in vivo. Erlotinib exhibited selective potent competitive inhibition against 4-MU glucuronidation by UGT1A1, and gefitinib demonstrated a wide range of inhibition against UGT-mediated 4-MU glucuronidation, particularly against UGT1A1, UGT1A7, UGT1A9, and UGT2B7. Erlotinib also exerted potent mixed inhibition against bilirubin glucuronidation in HLMs. We estimated that coadministration of erlotinib at 100 mg/day or higher doses may result in at least a 30% increase in the AUC of drugs predominantly cleared by UGT1A1. Thus, the coadministration of erlotinib with drugs primarily cleared by UGT1A1 may result in potential DDI. In contrast, gefitinib is unlikely to cause a clinically significant DDI through inhibition of glucuronidation.Erlotinib and gefitinib are potent, reversible, and selective inhibitors of the tyrosine kinase of the epidermal growth factor receptor. Both drugs have been approved for the treatment of patients with non-small-cell lung cancer, and erlotinib is also indicated for pancreatic cancer. In addition, phase II trials have suggested activity for these agents in a number of other solid tumors (Sequist and Lynch, 2008). Gefitinib and erlotinib share a common chemical backbone structure and exhibit similar oral bioavailability and disposition characteristics in humans after oral administration (Siegel-Lakhai et al., 2005).Drug-drug interactions (DDI) have received increasing attention over the past few decades. Several DDIs were reported to be associated with erlotinib and gefitinib. Coadministration of erlotinib has been reported to enhance the carboplatin exposure (Patnaik et al., 2006) and increase the serum concentration of phenytoin (Grenader et al., 2007). Drug interactions were also observed in two patients who received both gefitinib and warfarin simultaneously, which resulted in an enhancement of the warfarin effect (Onoda et al., 2005). Combination of gefitinib with capecitabine and radiation in patients with pancreatic and rectal cancer (Czito et al., 2006), as well as the combination of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer (Veronese et al., 2005), are associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.Metabolizing enzyme-based DDI constitute the major pro...

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UDP-Glucuronosyltransferase 1A1 Is the Principal Enzyme Responsible for Etoposide Glucuronidation in Human Liver and Intestinal Microsomes: Structural Characterization of Phenolic and Alcoholic Glucuronides of Etoposide and Estimation of Enzyme Kinetics

Cited by 71 publications

References 32 publications

Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids

Characterization of Human Hepatic and Extrahepatic UDP-Glucuronosyltransferase Enzymes Involved in the Metabolism of Classic Cannabinoids

P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases

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