<scp>UDP</scp>‐Glucuronosyltransferases: Pharmacogenetics, Functional Characterization, and Clinical Relevance

Foti, R.; Fisher, Michael B.

doi:10.1002/9780470921920.edm015

Cited by 4 publications

(4 citation statements)

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“…Previous studies have reported a significant correlation between UGT1A6/UGT1A9 expression using HLM . Correlations between UGT 1A6, 1A9 and 2B7 protein content may be explained by common regulatory factors including PXR, CAR, HNF‐1α and HNF‐4α . Additionally, UGT1A9 and UGT2B7 terminate the biological activity of arachidonic acid metabolites and hence are integral to the regulation of renal haemodynamics .…”

Section: Discussionmentioning

confidence: 98%

Scaling factors for the in vitro–in vivo extrapolation (IV–IVE) of renal drug and xenobiotic glucuronidation clearance

Knights

Spencer

Fallon

et al. 2016

Brit J Clinical Pharma

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AIMTo determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CL UGT ). METHODSMicrosomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CL int,u,UGT ) for PRO and morphine (MOR; 3-and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CL int,u,UGT on the prediction accuracy of the calculated CL UGT values of PRO and MOR. RESULTSMPPGK was 9.3 ± 2.0 mg g À1 (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2-and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg À1 ) was 2.7 fold higher than that reported for HLM. CONCLUSIONSScaled renal PRO glucuronidation CL int,u,UGT was double that of liver. Renal CL int,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Multiple drugs, non-drug xenobiotics and endobiotics are glucuronidated by human kidney.• UDP-glucuronosyltransferase (UGT) 1A proteins and UGT2B7 are variably expressed in the tubule components of the human nephron. • Development of kidney specific in vitro-in vivo extrapolation (IV-IVE) approaches is hampered by the limited availability of microsomal protein per gram of kidney (MPPGK) and knowledge of the content and anatomic distribution of individual UGT enzymes. WHAT THIS STUDY ADDS• This study provides scaling factors to assess the relative contribution of the kidney to renal drug clearance via glucuronidation.• It demonstrates anatomic differences in renal glucuronidation activity and provides data on the contents of UGT1A6, UGT1A9 and UGT2B7 in human kidney cortex and medulla.• It establishes that UGT1A9 is 2.7-fold more abundant in human kidney microsomes than hepatic microsomes, indicating the need to include renal glucuronidation unbound intrinsic clearance in IV-IVE predictions for substrates glucuronidated by UGT1A9. IntroductionThe human kidney has an array of functions that include the regulation of blood osmolarity, volume, ionic composition and pH, the production of renin, 1,25-dihydroxyvitamin D, erythropoietin, prostaglandins and bradykinin, and the excretion of endogenous metabolites and xenobiotics. The cortex is characterized by the presence of glomeruli, tufts of capillaries and numerous convoluted ...

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Section: Discussionmentioning

confidence: 98%

Scaling factors for the in vitro–in vivo extrapolation (IV–IVE) of renal drug and xenobiotic glucuronidation clearance

Knights

Spencer

Fallon

et al. 2016

Brit J Clinical Pharma

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“…Drug-metabolizing enzymes responsible for the phase II conjugative pathways include the UDPglucuronosyltransferases (UGTs), sulfotransferases, N-acetyltransferases, glutathione transferases, methyltransferases, and acyl-CoA synthetases. Examples of phase I and phase II enzymes, along with their respective cofactors, substrates, inhibitors, and tissue location, are shown in Tables 1 and 2 (Riddle and Jencks, 1971;Trager, 1989;Ghersi-Egea et al, 1993;Matsui and Homma, 1994;Riley and Hanzlik, 1994;Dutton, 1997;Rendic and Di Carlo, 1997;Burchell et al, 1998;Halpert et al, 1998;Burchell, 1999;Weinshilboum et al, 1999;Tukey and Strassburg, 2000;Dalvie et al, 2002;Ortiz de Montellano and De Voss, 2002;Coughtrie and Fisher, 2003;Ding and Kaminsky, 2003;Nelson and Trager, 2003;Guengerich, 2005;Satoh and Hosokawa, 2006;Cashman, 2008;Dourado et al, 2008;Nakamura et al, 2008;Decker et al, 2009;Remmel and Zhou, 2009;Strolin Benedetti, 2011;Fasinu et al, 2012;Foti and Fisher, 2012;Garattini and Terao, 2012). A number of comprehensive resources detailing the chemistry and reaction mechanisms for many of the enzymes are readily available (Trager, 1989;Riley and Hanzlik, 1994;Burchell et al, 1998;Halpert et al, 1998;Burchell, 1999;Dalvie et al, 2002;…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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“…With numerous pharmaceuticals such as propofol, irinotecan/SN-38 and opioids as well as many important endogenous compounds such as bilirubin, hormones, and bile acids known to undergo glucuronidation, in vitro systems capable of carrying out glucuronidation reactions have received a significant amount of attention in recent years [25,26]. …”

Section: Discussionmentioning

confidence: 99%

Evaluation of UGT protein interactions in human hepatocytes: Effect of siRNA down regulation of UGT1A9 and UGT2B7 on propofol glucuronidation in human hepatocytes

Konopnicki

Dickmann

Tracy

et al. 2013

Archives of Biochemistry and Biophysics

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Previous experiments performed in recombinant systems have suggested that protein–protein interactions occur between the UGTs and may play a significant role in modulating enzyme activity. However, evidence of UGT protein–protein interactions either in vivo or in more physiologically relevant in vitro systems has yet to be demonstrated. In this study, we examined oligomerization and its ability to affect glucuronidation in plated human hepatocytes. siRNA down regulation experiments and activity studies were used to examine changes in metabolite formation of one UGT isoform due to down regulation of a second UGT isoform. Selective siRNA directed towards UGT1A9 or UGT2B7 resulted in significant and selective decreases in their respective mRNA levels. As expected, the metabolism of the UGT1A9 substrate propofol decreased with UGT1A9 down regulation. Interestingly, UGT1A9 activity, but not UGT1A9 mRNA expression, was also diminished when UGT2B7 expression was selectively inhibited, implying potential interactions between the two isoforms. Minor changes to UGT1A4, UGT2B4 and UGT2B7 activity were also observed when UGT1A9 expression was selectively down regulated. To our knowledge, this represents the first piece of evidence that UGT protein–protein interactions occur in human hepatocytes and suggests that expression levels of UGT2B7 may directly impact the glucuronidation activity of selective UGT1A9 substrates.

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UDP‐Glucuronosyltransferases: Pharmacogenetics, Functional Characterization, and Clinical Relevance

Cited by 4 publications

References 461 publications

Scaling factors for the in vitro–in vivo extrapolation (IV–IVE) of renal drug and xenobiotic glucuronidation clearance

Scaling factors for the in vitro–in vivo extrapolation (IV–IVE) of renal drug and xenobiotic glucuronidation clearance

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Evaluation of UGT protein interactions in human hepatocytes: Effect of siRNA down regulation of UGT1A9 and UGT2B7 on propofol glucuronidation in human hepatocytes

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