C-440T/T-331C Polymorphisms in the
            <i>UGT1A9</i>
            Gene Affect the Pharmacokinetics of Mycophenolic Acid in Kidney Transplantation

Baldelli, Sara; Merlini, Simona; Perico, Norberto; Nicastri, Annalisa; Cortinovis, Monica; Gotti, Eliana; Remuzzi, Giuseppe; Cattaneo, Dario

doi:10.2217/14622416.8.9.1127

Cited by 89 publications

(74 citation statements)

References 47 publications

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“…Several reports have found that the pharmacokinetics of MPA in humans is characterized by large inter-and intraindividual variability and that glucuronide activity from MPA may be involved in the between-individual variability (Kuypers et al, 2005;Baldelli et al, 2007). In the present study, we focused on the importance of the MMF bioactivation pathway to MPA as a factor other than the MPA glucuronidation pathway previously researched.…”

Section: Discussionmentioning

confidence: 95%

Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Fujiyama¹,

Miura²,

Kato³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Mycophenolate mofetil (MMF) is the ester prodrug of the immunosuppressant agent mycophenolic acid (MPA) and is rapidly activated by esterases after oral administration. However, the role of isoenzymes in MMF hydrolysis remains unclear. Although human plasma, erythrocytes, and whole blood contain MMF hydrolytic activities, the mean half-lives of MMF in vitro were 15.1, 1.58, and 3.20 h, respectively. Thus, blood esterases seemed to contribute little to the rapid MMF disappearance in vivo. In vitro analyses showed that human intestinal microsomes exposed to 5

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Section: Discussionmentioning

confidence: 95%

Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Fujiyama¹,

Miura²,

Kato³

et al. 2010

Drug Metab Dispos

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“…In addition to these SNPs, Baldelli et al . [112] have also shown that −440 C>T and −331 T>C SNPs of the UGT1A9 promoter region were associated with an increased systemic exposure to MPA in renal transplant patients. Besides UGT1A9, the role of genetic polymorphisms in other UGTs on MPA pharmacokinetics is less clear.…”

Section: Genetic Polymorphismmentioning

confidence: 89%

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

Dalvie

Loi

2012

Encyclopedia of Drug Metabolism and Interactions

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Uridine 5′‐diphosphate‐glucuronosyltransferases (UGT) are a family of enzymes that catalyze the conjugation of various drugs and endogenous substances. UGTs contribute to multiple important physiologic functions in the body and serve as an important detoxification pathway for certain drugs. In addition to their abundance in the liver and kidneys, UGTs are also expressed in several other organs including the GI tract. Given their importance in the disposition of drugs and their ubiquitous nature, they have the potential to influence the pharmacokinetics and biological effects of drugs. In addition to detoxification, UGTs are also responsible in metabolically activating compounds to reactive metabolites such as the acyl glucuronides that have the potential to covalently bind to macromolecules and elicit deleterious effects. As the cytochrome P450s (CYPs), UGTs are also subject to genetic polymorphisms and drug‐drug interactions (DDIs), which can impact the clinical development of drugs. This chapter presents an overview of the role and clinical consequences of metabolism of drugs by UGT.

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“…Thus, edaravone has a high affinity toward UGT1A9 and may have the potential to inhibit the glucuronidation of UGT1A9 substrates. In addition, genetic polymorphisms of UGT1A9 have been implicated in the interindividual variation of mycophenolic acid metabolism (Kuypers et al, 2005;Baldelli et al, 2007;Sánchez-Fructuoso et al, 2009). The relationships between UGT1A9 polymorphisms and edaravone metabolism have never been mentioned before, but they should be paid more attention.…”

Section: Glucuronidation Of Edaravone By Hlm and Hkmmentioning

confidence: 99%

Glucuronidation of Edaravone by Human Liver and Kidney Microsomes: Biphasic Kinetics and Identification of UGT1A9 as the Major UDP-Glucuronosyltransferase Isoform

Ma¹,

Sun²,

Peng³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Edaravone was launched in Japan in 2001 and was the first neuroprotectant developed for the treatment of acute cerebral infarction. Edaravone is mainly eliminated as glucuronide conjugate in human urine (approximately 70%), but the mechanism involved in the elimination pathway remains unidentified. We investigated the glucuronidation of edaravone in human liver microsomes (HLM) and human kidney microsomes (HKM) and identified the major hepatic and renal UDP-glucuronosyltransferases (UGTs) involved. As we observed, edaravone glucuronidation in HLM and HKM exhibited biphasic kinetics. The intrinsic clearance of glucuronidation at high-affinity phase (CL int1 ) and low-affinity phase (CL int2 ) were 8. , respectively, for HLM and were 78.5 ؎ 3.9 and 3.6 ؎ 0.5 l ⅐ min ؊1 ⅐ mg ؊1, respectively, for HKM. Screening with 12 recombinant UGTs indicated that eight UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17) produced a significant amount of glucuronide metabolite. Thus, six UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A9, UGT2B7, and UGT2B17) expressed in human liver or kidney were selected for kinetic studies. Among them, UGT1A9 exhibited the highest activity (CL int1 ‫؍‬ 42.4 ؎ 9.5 l ⅐ min ؊1 ⅐ mg

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C-440T/T-331C Polymorphisms in the UGT1A9 Gene Affect the Pharmacokinetics of Mycophenolic Acid in Kidney Transplantation

Abstract: The study demonstrated a significant impact of C-440T/T-331C SNPs in the promoter region of the UGT1A9 gene on MPA pharmacokinetics in renal allograft recipients.

Cited by 89 publications

References 47 publications

Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

Glucuronidation of Edaravone by Human Liver and Kidney Microsomes: Biphasic Kinetics and Identification of UGT1A9 as the Major UDP-Glucuronosyltransferase Isoform

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