In vitro–in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: Pitfalls and promises

Miners, John O.; Knights, Kathleen M.; Houston, J. Brian; Mackenzie, Peter I.

doi:10.1016/j.bcp.2005.12.019

Cited by 209 publications

(121 citation statements)

References 65 publications

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“…UGT1A3, UGT1A9, and UGT2A1 are the major enzymes of the conjugation of carboxylic acids, UGT1A4 and UGT1A3 catalyze the N-glucuronidation of amines. UGT1A6 preferentially conjugates complex phenols and primary amines 10,20,23 . The selectivity of UGT1A3 toward carboxylic acid-containing compounds (aliphatic or aromatic) has also been described 24 .…”

Section: Substrates Inhibitors and Inductors Of Ugtsmentioning

confidence: 99%

Phase Ii Drug Metabolizing Enzymes

Jančová¹,

Anzenbacher²,

Anzenbacherová³

2010

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

467

347

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Section: Substrates Inhibitors and Inductors Of Ugtsmentioning

confidence: 99%

Phase Ii Drug Metabolizing Enzymes

Jančová¹,

Anzenbacher²,

Anzenbacherová³

2010

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

467

347

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“…The UGT enzymes of each family share at least 40% homology in DNA sequence, whereas members of UGT subfamilies exert at least 60% identity in DNA sequence (Burchell et al, 1995). As of the time of writing, 22 human UGT proteins can be distinguished: UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, UGT2A2, UGT2A3, UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, UGT2B17, UGT2B28, UGT3A1, UGT3A2, and UGT8A1 (Mackenzie et al, 2008;Miners et al, 2006;Court et al, 2004;Patten, 2006;Sneitz et al, 2009). In general, human UGT enzymes apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many UGTs.…”

Section: Human Forms Of Ugts and Their Tissue Distributionmentioning

confidence: 99%

Phase II Drug Metabolism

Jančová¹,

Siller²

2012

Topics on Drug Metabolism

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“…This may be partly due to the fact that the contributions of the major metabolic pathways to fibrate clearance have not been systematically investigated. Previous in vitro studies generally focused on a specific pathway by adding either NADPH or UDPGA to initiate oxidative or conjugated reactions [22,29]. Such strategies may hence underestimate the true metabolic rate of fibrates when using in vitro-in vivo extrapolation studies because the contribution of both pathways should not be ignored.…”

Section: Discussionmentioning

confidence: 99%

“…Much attention has been placed on the optimization of in vitro incubation conditions [18][19][20]. However, the in vitro-in vivo extrapolation generally underestimates the metabolism of agents metabolized by multiple pathways [21,22]. One reason for this is that the phase I and phase II metabolic pathways are investigated individually.…”

mentioning

confidence: 99%

Metabolism of fibrates by cytochrome P450s and UDP-glycosyltransferases in rat and human liver microsomes

et al. 2012

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Fibrates are widely used for the treatment of dyslipidemia. However, the contributions of the phase I and phase II metabolic pathways to the clearance of fibrates are unclear. In this study, we investigated the metabolism of gemfibrozil (Gem), clofibric acid (CA), fenofibric acid (FA) and bezafibrate (Beza) by cytochrome P450s (P450s) and UDP-glycosyltransferases (UGTs) using a substrate depletion approach. We also compared the metabolic characteristics of rat liver microsomes (RLM) and human liver microsomes (HLM). The intrinsic clearance rates mediated by P450s, UGTs and both were 172 ± 22, 643 ± 26, 798 ± 103 µL min -1 mg -1, respectively, for Gem and 43 ± 11, 88 ± 12, 119 ± 15 µL min -1 mg -1 , respectively, for CA in RLM. The fractions metabolized by P450s and UGTs in RLM were 22% and 81% for Gem, 36% and 74% for CA. The P450-and UGT-mediated depletion rates for Gem were 303 and 1607 nmol min -1 mg -1 in RLM versus 86 and 243 nmol min -1 mg -1 in HLM. The corresponding rates for CA were 1.1 and 1.7 nmol min -1 mg -1 in RLM versus 0.025 and 0.038 nmol min -1 mg -1 in HLM. Accordingly, both P450s and UGTs substantially contribute to the clearance of Gem and CA, with UGTs playing a greater role. To avoid under-estimating the impact of these pathways, it is necessary to measure NADPH-and UDPGA-dependent metabolism. Although the fractions of these two pathways in RLM and HLM were similar, the depletion rate of Gem and CA in RLM was higher than that in HLM. The metabolism of FA and Beza by P450s and UGTs was too low to calculate intrinsic clearance in both RLM and HLM. These results indicate that fibrates are metabolized via similar pathways in rats and humans, and it is applicable to use RLM to predict the clearance of fibrates in human.

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In vitro–in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: Pitfalls and promises

Cited by 209 publications

References 65 publications

Phase Ii Drug Metabolizing Enzymes

Phase Ii Drug Metabolizing Enzymes

Phase II Drug Metabolism

Metabolism of fibrates by cytochrome P450s and UDP-glycosyltransferases in rat and human liver microsomes

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