Quantitative Prediction of Human Intestinal Glucuronidation Effects on Intestinal Availability of UDP-Glucuronosyltransferase Substrates Using In Vitro Data

Nakamori, Fumihiro; Naritomi, Yoichi; Hosoya, Ken‐ichi; Moriguchi, Hiroyuki; Tetsuka, Kazuhiro; Furukawa, Takako; Kadono, Kohei; Yamano, Katsuhiro; Terashita, Shigeyuki; Teramura, Toshio

doi:10.1124/dmd.112.045476

Cited by 13 publications

(6 citation statements)

References 33 publications

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“…27) Therefore, a pan-UGT inhibitors would also be beneficial for drug discovery. Nakamori et al have reported that quercetin was metabolized by 12 different subtypes of UGT-overexpressed supersomes including the UGT1A and 1B family, 28) postulating quercetin as a potential pan-inhibitor to UGT metabolism. The present study revealed that quercetin can reduce both MPAG and AcMPAG accumulation in SCH with a concomitant increase in MPA accumulation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Tetsuka¹,

Gerst²,

Tamura³

et al. 2014

Drug Metabolism and Pharmacokinetics

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Rat sandwich-cultured hepatocytes (SCH) were used to correlate the in vitro hepatic disposition of mycophenolic acid (MPA) with published in vivo data, as well as mechanistic studies on drug-drug interaction. The major metabolite of MPA in SCH was 7-O-glucuronide (MPAG) followed by acyl-glucuronide (AcMPAG). MPAG and AcMPAG, but not MPA, showed significant in vitro biliary excretion with biliary excretion indexes (BEI) of 40% for MPAG and 45% for AcMPAG. While these BEIs were similar, the biliary excretion amount (BEA) of MPAG (120 pmol/mg protein) was orders of magnitude higher than that of AcMPAG (0.34 pmol/mg protein). Since MPAG is the major metabolite in in vivo bile, we propose that BEA is a better qualifier of biliary excretion. Quercetin inhibited MPAG and AcMPAG production, while chrysin inhibited only MPAG production, showing that chrysin is not a pan-glucuronidation inhibitor. Cyclosporin A (CysA) reduced the BEI of MPAG and increased intracellular MPA accumulation without changing MPAG amounts. These results suggest that CysA causes inhibition of biliary excretion of MPAG, as well as a mixed inhibition of glucuronidation of MPA and sinusoidal efflux of MPA/MPAG. In conclusion, the present study demonstrates a good agreement of hepatic MPA disposition between SCH and in vivo rats.

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Section: Discussionmentioning

confidence: 99%

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Tetsuka¹,

Gerst²,

Tamura³

et al. 2014

Drug Metabolism and Pharmacokinetics

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“…The K i value of telmisartan for CPT-11 hydrolysis by HLM (1.2 6 0.1 mM) was 10-fold higher than the estimated concentration of telmisartan in the liver. In contrast, the concentration of telmisartan in the intestine in which CES2 is highly expressed was predicted to be 31 mM (Nakamori et al, 2012). Thus, telmisartan may exhibit a DDI with compounds that are substrates of CES2 via inhibition of CES2 in the intestine but not in the liver.…”

Section: Downloaded Frommentioning

confidence: 97%

Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

et al. 2014

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Esterases catalyze the hydrolysis of therapeutic drugs containing esters or amides in their structures. Human carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes that catalyze the hydrolysis of drugs in the liver. Characterization of the enzyme(s) responsible for drug metabolism is required in drug development and to realize optimal drug therapy. Because multiple enzymes may show a metabolic potency for a given compound, inhibition studies using chemical inhibitors are useful tools to determine the contribution of each enzyme in human tissue preparations. The purpose of this study was to find specific inhibitors for human CES1, CES2, and AADAC. We screened 542 chemicals for the inhibition potency toward hydrolase activities of p-nitrophenyl acetate by recombinant CES1, CES2, and AADAC. We found that digitonin and telmisartan specifically inhibited CES1 and CES2 enzyme activity, respectively. Vinblastine potently inhibited both AADAC and CES2, but no specific inhibitor of AADAC was found. The inhibitory potency and specificity of these compounds were also evaluated by monitoring the effects on hydrolase activity of probe compounds of each enzyme (CES1: lidocaine, CES2: CPT-11, AADAC: phenacetin) in human liver microsomes. Telmisartan and vinblastine strongly inhibited the hydrolysis of CPT-11 and/or phenacetin, but digitonin did not strongly inhibit the hydrolysis of lidocaine, indicating that the inhibitory potency of digitonin was different between recombinant CES1 and liver microsomes. Although we could not find a specific inhibitor of AADAC, the combined use of telmisartan and vinblastine could predict the responsibility of human AADAC to drug hydrolysis.

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“…2 ) can be relatively straightforward and ‘minimal’ models, such as Q Gut , require only in vitro metabolic CL int and cell permeability data to estimate F G . Several groups have reported successful prediction of F G in animals [ 242 , 243 ] and humans [ 49 , 227 , 228 , 244 , 245 ] with this approach. Drugs with high in vivo extractions ( F G values <0.5) were less accurately predicted and may reflect inability of the Q Gut model to account for changes in enterocyte drug concentration and therefore saturation of DME and efflux transporter processes [ 246 ].…”

Section: Preclinical Models For the Prediction Of F mentioning

confidence: 99%

Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models

et al. 2016

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Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models—in vivo, in situ and in vitro—have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.

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Quantitative Prediction of Human Intestinal Glucuronidation Effects on Intestinal Availability of UDP-Glucuronosyltransferase Substrates Using In Vitro Data

Cited by 13 publications

References 33 publications

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models

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