1. Medicine

Hepatoenteric recycling is a new disposition mechanism for orally administered phenolic drugs and phytochemicals in rats

  1. Yifan Tu
  2. Lu Wang
  3. Yi Rong
  4. Vincent Tam
  5. Taijun Yin
  6. Song Gao
  7. Rashim Singh
  8. Ming Hu  Is a corresponding author
  1. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, United States
  2. Department of Pharmaceutical Sciences, College of Pharmacy, Texas Southern University, United States
https://doi.org/10.7554/eLife.58820
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Cite this article
  1. Yifan Tu
  2. Lu Wang
  3. Yi Rong
  4. Vincent Tam
  5. Taijun Yin
  6. Song Gao
  7. Rashim Singh
  8. Ming Hu
(2021)
Hepatoenteric recycling is a new disposition mechanism for orally administered phenolic drugs and phytochemicals in rats
eLife 10:e58820.
https://doi.org/10.7554/eLife.58820
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6 figures, 13 tables and 1 additional file

Figures

Figure 1
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The pictorial representation of the newly proposed mechanism of hepatoenteric (HER) recycling and conventional mechanism of enterohepatic recycling/recirculation (EHR).

(A). HER starts from intestinal glucuronidation of orally dosed aglycones. The glucuronides are taken up into the hepatocytes via portal vein using hepatic uptake transporter OATPs, and then excreted back into bile by apical hepatic efflux transporters, allowing them to return to the small intestine. For biliary glucuronides, the gut microflora β-glucuronides (GUS) will hydrolyze them back into the aglycone form, which are then reabsorbed in colon to complete the recycling. (B) EHR starts from the hepatic metabolism of an aglycone entering liver (from intestinal absorption or blood circulation) into its phase II metabolites (mostly glucuronides). The glucuronides formed in the liver are excreted into bile by the apical hepatic efflux transporters,returned to the small intestine and then moved to colon, where the gut microflora GUS hydrolyze them back into the aglycone form. The aglycone is then re-absorbed from colon and reached the liver again to complete the EHR.

Figure 2 with 3 supplements
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Effect of the glucuronide concentrations, aglycone structures, and aglycone concentrations on the biliary secretion, systemic exposure and liver recycling efficiency (LRE%) in a rat portal vein infusion model.

Following portal vein infusion of Won-7-G at various concentrations (2–1000 μM), amounts of glucuronide excreted into bile (A1), concentrations of glucuronide in blood (A2) and LRE% (A3) were determined, and then the biliary secretion rates of glucuronides were plotted against their steady-state blood concentrations (A4). After the hepatic infusion of seven different aglycones [Won; Api; Bai; Lut; Ral; and Eze] and their corresponding glucuronides [Won-7-G; Api-7-G; Bai-7-G; Lut-3’-G; Ral-6-G; Ral-4’-G and Eze-4’-G] at 10 μM concentration, amount of the glucuronides secreted in bile during portal vein infusion of aglycones versus glucuronides were determined (B1–B7). Following the portal vein infusion of Won at 2 μM for the first 2.5 hr and at 100 μM for next 2 hr, the amount of Won-7-G secreted in bile (C1), the accumulated amount of Won-7-G secreted in bile (C2), and LRE% (C3) at low (2 μM) and high (100 μM) concentrations of Won were compared to study the effect of protein binding of Won on its liver uptake. The liver concentrations of Won and Won-7-G could be found in Appendix 2—table 2. 4. Four male Wistar rats were used in each experimental group. Statistical significance was calculated using student t test ('*', '**', and '***' indicates p<0.05, p<0.01, and p<0.001, respectively).

Figure 2—figure supplement 1
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The bile amount and accumulative bile amount of Won-7-G.

(A,B) and Lut-3’-G (C,D) obtained from single infusion and combo infusion (four compounds infused simultaneously at 10 μM) were summarized. N = 4 in each experimental group. Student t test was applied and no statistical significance exists between single infusion group and combo infusion group.

Figure 2—figure supplement 2
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The microsome incubation and hydrolysis of Lut and its glucuronides.

(A) The hydrolysis of microsome incubation samples was summarized in Fig. 2 supplement figure S2. After incubating the microsome samples with β-glucuronidase, the peak of Lut-3’-G and Lut-di-G decreased and the peak of Lut increased.Appendix 5—table 1 The results comfirmed the existing of di-glucuronidation metabolite. (B) The UV spectrum of Lut-3’-G after incubation with microsome. (C) The UV spectrum of Lut-3’-G microsome sample after 30 min of hydrolysis.

Figure 2—figure supplement 3
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The blood concentration-time curve of Won-7-G(A), Bai-7-G(B), Eze-4’-G(C) and Ace-G(D) after orally administration of their corresponding aglycones, n = 4.

The compounds were given at 30 mg/kg by oral gavage. Blood samples were taken at 0, 0.5, 1, 2, 4, 6, 8, and 24 hr after compound administration.

Figure 3
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The OATP uptake kinetics, and the effect of glucuronide structures and uptake inhibitors on the hepatic uptake of glucuronides by OATP1B1/1B3/2B1 in over-expressed cell lines.

Intracellular concentration of glucuronides obtained using 1 μM of 10 different glucuronides [Won-7-G; E2G; Bai-7-G; Que-3-G; Scu-7-G; Api-7-G; Lut-7-G; Lut-3’-G; Eze-4’-G; and E2S] (A) was determined (10 μM was used in OATP 2B1 but results were normalized to 1 μM). Uptake kinetics of Won-7-G (B1), Api-7-G (B2), Lut-3’-G (B3) and Eze-4’-G (B4) in the concentration range of 0.5–50 µM in OATP1B1/1B3/2B1 over-expressed cell lines were determined. Km and Vmax values were calculated using Michaelis-Menten kinetics and summarized in Appendix 2—table 7. Effect of OATP inhibitors (50 μM rifampicin as OATP1B1/1B3 inhibitor and 50 μM erlotinib as OATP2B1 inhibitor) on the cellular uptake of five different glucuronides (E2G for OATP1B1/1B3 and E1S for OATP2B1 as positive controls) in OATP1B1 (C1), OATP1B3 (C2), and OATP2B1 (C3) over-expressed cell lines was studied at 10 μM substrate concentration (Figure 3C1–C3). Cross-over uptake in OATP1B1 cells using 1 μM of Won-7-G, E2G, Lut-3’-G as substrates was studied and intracellular concentrations of the glucuronides were determined in absence and presence of 25 μM of other aglycones and glucuronides as inhibitors. Each experiment was run in triplicate using substrates solutions in HBSS buffer (pH 7.4) at 37°C and the incubation lasted for 20 min. Statistical significance was calculated using student t test in Figure 3B1–B3 and one-way ANOVA in Figure 3A and C1–C ('*', '**', and '***' indicates p<0.05, p<0.01, and p<0.001, respectively).

Figure 4 with 3 supplements
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Correlation of liver recycling efficiency (LRE%) and intracellular concentration of glucuronides.

LRE% of 16 glucuronides calculated based on rat portal vein infusion experiment were plotted against the intracellular concentrations calculated as the sum of the individual measured intracellular concentrations in OATP1B1, 1B3, and 2B1 cells in the OATP uptake studies, weighted by their protein expression levels in human liver using Emax model. The Emax and EC50 parameter values were estimated and summarized in the table below the graph.

Figure 4—figure supplement 1
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The elimination half-life of Won-7-G, Bai-7-G, Eze-4’-G, and Ace-G were plotted against with their corresponding liver recycling efficiency (LRE), n = 4.

Pharmacokinetic parameters were calculated by noncompartmental analysis (Phoenix WinNonlin 8.0; Pharsight, St. Louis, MO). The terminal elimination constant was obtained from the least-squares linear regression slope of concentration versus time, and terminal elimination half-life was calculated as 0.693/k.

Figure 4—figure supplement 2
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The relative blood stability of Won-7-G, Bai-7-G, and Api-7-G at three concentrations (2, 10,and 25 μM).

One-way Anova was applied and no significant differences were found.

Figure 4—figure supplement 3
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The blood concentration-time curve of Won (A), Bai (B), Eze (C), and Ace (D) after orally administration of the aglycones, n = 4.

The aglycones were given at 30 mg/kg by oral gavage. Blood samples were taken at 0, 0.5, 1, 2, 4, 6, 8, and 24 hr after compound administration.

Figure 5
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Differences in the portal vein and systemic concentrations of glucuronides after the intestinal perfusion of aglycone.

five aglycones [Eze; Won; Ral; Api and Bai] were perfused in the rat small intestine (duodenum and jejunum, approximate length = 15 cm) individually at the rate of 24 nmol/hr for 2.5 hr in male Wistar rats (n = 4 per experimental group). Bile and intestinal perfusate samples were collected for every 30 min. Blood samples from tail vein and portal vein were collected at the end of the study and analyzed for the concentration of respective glucuronides. The absorption percentage of each aglycone were calculated and tabulated below the graph in the figure. The biliary secretion of the glucuronides was summarized in Table 1. Statistical significance was calculated using student t-test ('*', '**', and '***' indicates p<0.05, p<0.01, and p<0.001, respectively).

Figure 6
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Effect of hepatic uptake inhibitors on the biliary excretion of glucuronides.

A combination of four hepatic uptake inhibitors (rifampicin, telmisartan, estradiol-17β-glucuronide and estrone-3-sulfate) at 1 mM concentration were infused in rat portal vein for an hour as pretreatment, followed by co-infusion of inhibitors (at 1 mM) and glucuronide substrate [Won-7-G or Lut-3’-G] (at 10 µM) in the rat portal vein at the rate of 2 ml/hr for 2.5 hr in male Wistar rats (n = 4 per group). The bile amounts of Won-7-G (A), Lut-3’-G (B) and the accumulated bile amounts of Won-7-G (C), Lut-3’-G (D) with or without the uptake inhibitors were determined. Statistical significance was calculated by student t test (‘**” indicates p<0.01).

Tables

Table 1
Comparison of bililary secretion rates and liver recycling efficiency (%) of glucuronides following hepatic glucuronide infusion, hepatic aglycone infusion, and small intestinal aglycone perfusion.

The rate of hepatic infusion was 20 nmol/hr and the rate of intestinal perfusion was 24 nmol/hr.

Dosing methodHepatic glucuronide infusionHepatic aglycone infusionSmall intestine aglycone perfusion
Infused compoundsEze-4'-GEzetimibe (Eze)Ezetimibe (Eze)
Won-7-GWongonin (Won)Wongonin (Won)
Ral-6-GRaloxifene (Ral)Raloxifene (Ral)
Api-7-GApigenin (Api)Apigenin (Api)
Bai-7-GBaicalein (Bai)Baicalein (Bai)
Measured compoundBile secretion rate(nmol/hr)
Eze-4'-G19.31 ± 1.852.93 ± 0.41***,†21.94 ± 5.29
Won-7-G16.30 ± 4.288.46 ± 3.93***,†17.90 ± 11.96
Ral-6-G10.53 ± 1.513.91 ± 0.82***4.00 ± 0.68
Api-7-G10.64 ± 4.491.22 ± 0.76***,†11.32 ± 4.08
Bai-7-G0.69 ± 0.290.09 ± 0.07***,†ND†
Measured compoundLRE(%)
Eze-4'-G96.54 ± 9.2314.65 ± 0.02***,†91.42 ± 22.04
Won-7-G81.5 ± 21.4142.30 ± 0.20***,†74.58 ± 49.83
Ral-6-G52.64 ± 7.5419.55 ± 0.04***,†16.67 ± 2.83
Api-7-G53.21 ± 22.446.10 ± 0.04***,†47.17 ± 17.00
Bai-7-G3.43 ± 1.460.45 ± 0.35***,†ND‡

  1. *Significant difference between hepatic glucuronide infusion and hepatic aglycone infusion, p<0.01.

    †Significant difference between hepatic aglycone infusion and small intestinal perfusion , p<0.01.

  2. ‡Not determined due to below quantification limit.

Appendix 1—key resources table
Reagent type (species) or resourceDesignationSource or referenceIdentifiersAdditional information
Chemical compound, drugApigenin-7-O-glucuronide (Api-7-G)HWI Analytik GmbHLot#: 0449059
Chemical compound, drugWogonoside (Won-7-G)Meilun bioMB6662
Chemical compound, drugQuercetin (Que-3-G)Sigma-Aldrich00310590
Chemical compound, drugScutellarin (Scu-7-G)MeilunebioMB7004-S
Chemical compound, drugLuteolin-3’-glucuronide (Lue-3’-G)Chengdu Alfa Biotechnology Co.,Ltd.AF8025306
Chemical compound, drugLuteolin-7-glucuronide (Lue-7-G)Chengdu Alfa Biotechnology Co.,Ltd.Af7022398
Chemical compound, drugWogonin (Won)MeilunebioMB6663
Chemical compound, drugLuteolin (Lue)MeilunebioMB6799
Chemical compound, drugIcaritin (Ica)MeilunebioMB7035
Chemical compound, drugIcaritin-3-glucuronide (Ica-3-G)This compound was synthesized by our cooperative lab.
Chemical compound, drugIcaritin-7-glucuronide (Ica-7-G)This compound was synthesized by our cooperative lab.
Chemical compound, drugEstradiol-17β-glucuronide (E2G)Steraloids CompanyE1073-000
Chemical compound, drugEstrone-3-sulfate (E1S)Steraloids CompanyE2335-000
Chemical compound, drugRaloxifene (Ral)Toronto Research ChemicalR099995
Chemical compound, drugRaloxifene-4’-glucuronide (Ral-4’-G)Toronto Research ChemicalR100020
Chemical compound, drugRaloxifene-6-glucuronide (Ral-6-G)Toronto Research ChemicalR100025
Chemical compound, drugEzetimibe (Eze)Toronto Research ChemicalE975000
Chemical compound, drugEzetimibe-4’-phenoxy-glucuronide (Eze-4’-G)Toronto Research ChemicalE975030
Chemical compound, drugApigenin (Api)IndofineA-002
Chemical compound, drugBaicalein (Bai)IndofineB-101
Chemical compound, drugBaicalein-7-glucuronide (Bai-7-G)Indofine06–012
Chemical compound, drugDimethyl sulfoxide (DMSO)Sigma-Aldrich276855
Chemical compound, drugHanks balanced salt solution (HBSS)Sigma-AldrichH1387
Chemical compound, drugAcetonitrile (ACN)Omni SolvAX0149
Chemical compound, drugmethanol (MeOH)Omni SolvMX0486
Chemical compound, drugORA-Plus suspending vehiclePerrigo0574-0303-16
Cell line (Homo-sapiens)HEK-293 OATP1B1/1B3 over-expressed cell lineDr.Yue Wei’s LabThe related publication could be searched by using PMID:29538325
Cell line (Homo-sapiens)HEK-293 OATP2B1 over-expressed cell lineDr. Per Artursson’s LabThe related publication could be searched by using
PMID:24799396
Software, algorithmGraphPad Prism 6GraphPad Software IncRRID:SCR_002798
Appendix 2—table 1
The hepatic expression level of OATP 1B1/1B3/2B1.

Expression level was presented as average ± SD. Data was obtained from Pubmed Gene database.

TransporterOATP 1B1*OATP 1B1†OATP 2B1‡
Expression (RPKM)119.3 ± 20.830.2 ± 3.944.0 ± 4.1
Relative expression (%)61.715.622.7

  1. *https://www.ncbi.nlm.nih.gov/gene/10599.

    † https://www.ncbi.nlm.nih.gov/gene/28234.

  2. ‡ https://www.ncbi.nlm.nih.gov/gene/11309.

Appendix 2—table 2
The uptake of wogonin in four different cell lines.

The incubation concentration, time, condition and intracellular concentrations were summarized in the table. Inhibitor(s) were changed in different cell line. For OATP1B1 and OATP1B3 cell line, inhibitor was 50 μM rifampicin. For OATP 2B1 cell line, inhibitor was 50 μM telmisartan. For MDCK cell line, inhibitors were 50 μM rifampicin and 50 μM telmisartan. Student t test was applied to calculate the p values. No significant differences observed when wogonin was incubated with or without inhibitor.

Cell typeIncubation concentration(μM)Incubation time(min)InhibitorIntracellular concentration(nM)
MDCK MRP3 over-expressed cell line5120Yes150.33 ± 37.87
5120No163.67 ± 21.57
HEK-293 OATP1B1 over- expressed cell line1020Yes442.00 ± 309.56
1020No365.67 ± 168.67
HEK-293 OATP1B3 over- expressed cell line1060Yes333.33 ± 33.08
1060No381.33 ± 128.82
HEK-293 OATP2B1 over- expressed cell line1020Yes782.33 ± 115.42
1020No897.00 ± 409.17
Appendix 2—table 3
The uptake of wogonin and wogonin-7-G (wogonoside) in three different cell lines.

The incubation concentration, time, condition and intracellular concentrations were summarized iin the table. Inhibitor(s) were changed in different cell line. For OATP1B1 and OATP1B3 cell line, inhibitor was 50 μM rifampicin. For OATP 2B1 cell line, inhibitor was 50 μM telmisartan. Student t test was applied to calculate the p values. Significant differences were observed when wogonoside incubated with or without inhibitors in OATP 1B1 and 1B3 cell lines. No significant differences observed when wogonin was incubated with or without inhibitor.

Cell typeIncubation concentration (μM)Incubation time (min)InhibitorWogonoside intracellular concentration
(nM)		Wogonin intracellular concentration
(nM)
HEK-293 OATP1B1 over- expressed cell line1020Yes0.01 ± 0.01442.00 ± 309.56
1020No401.00 ± 29.60††365.67 ± 168.67
HEK-293 OATP1B3 over- expressed cell line1060Yes48.33 ± 9.12333.33 ± 33.08
1060No58.03 ± 16.60381.33 ± 128.82
HEK-293 OATP2B1 over- expressed cell line1020Yes34.57 ± 21.26782.33 ± 115.42
1020No82.87 ± 2.45*897.00 ± 409.17

  1. *p< 0.05.

    †p<0.01.

Appendix 2—table 4
The liver concentration of wogonin/wogonin-7-G (n = 3).
CompoundWogoninWogonin-7-G (Wogonoside)
Liver concentration
(nmol/g)		0.51 ± 0.28<0.1*
Ratio (Wogonin/Wogonoside)5 >\

  1. * The concentration was below quantification limit (4 nM).

Appendix 2—table 5
Biliary glucuronide secretion rate and liver recycling efficiency of 16 different glucuronides.
Infused compound (10 μM)Secretion rate (nmol/hr)*LRE%†
Ezetimibe-4'-G19.31 ± 1.8596.5 ± 9.2
Wogonin-7-G(wogonoside)16.3 ± 4.2881.5 ± 21.4
Genestein-7-G9.78 ‡59.3 ‡
Raloxifene-4'-G11.48 ± 2.3257.4 ± 11.6
Apigenin-7-G10.64 ± 4.4953.2 ± 22.4
Raloxifene-6-G10.53 ± 1.5152.6 ± 7.5
Chrysin-7-G9.86 ‡49.3 ‡
Icaritin-7-G7.46 ± 0.7237.3 ± 3.6
Biochanin A-G3.28 ‡27.8 ‡
Icaritin-3-G5.35 ± 1.1226.8 ± 5.6
Scuttelarin4.34 ± 1.1821.7 ± 5.9
Luteolin-3’-G1.33 ± 0.346.7 ± 1.7
Baicalin0.69 ± 0.303.4 ± 1.5
Luteolin-7-glycoside0.67 ± 0.563.4 ± 2.8
Quercetin-3-G0.43 ± 0.572.2 ± 2.8
Ace-G0.10 ± 0.060.5 ± 0.3

  1. *The glucuronide secretion rate at the steady state was calculated by the linear regression of accumulated amount secreted in bile vs. time.

    † LRE (liver recycling efficiency) % = Secretion rate at steady state infuse rate.

  2. ‡ Data from previous published study (Zeng et al., 2016).

Appendix 2—table 6
Gender differences in bile secretion rates and liver recycling efficiency (LRE%).
Infusion compounds
(10 μM)		Secretion rate (nmol/hr)LRE(%)
MaleFemaleMaleFemale
Won-7-G16.30 ± 4.2815.06 ± 0.7081.5 ± 21.475.3 ± 3.5
Bai-7-G0.69 ± 0.291.78 ± 0.423.4 ± 1.58.9 ± 2.1
Lut-3'-G1.33 ± 0.341.67 ± 0.326.7 ± 1.78.3 ± 1.6
Appendix 2—table 7
Kinetic parameters of uptake (Km and Vmax) of selected glucuronides wogonoside, luteolin-3’-glucuronide (Lut-3’-glu) and apigenin-7-glucuronide (Api-7-glu) in OATP1B1/1B3/2B1 over-expressed cells.
Compound1B11B32B1
Km(μM)Vmax
(pmol/min)		Km(μM)Vmax
(pmol/min)		Km(μM)Vmax
(pmol/min)
Won-7-G27.6853.37>5011.72>5055.26
Lut-3’-G4.4622.79>509.620.894.07
Api-7-G>50>200>50>2009.725.09
Eze-4'-G>5011.4517.641.678.551.61
Appendix 3—table 1
Compound-dependent parameter of the analytes and I.S.
CompoundQ1/Q3DPCEEPCXP
Api-7-G445.0/269.0−90−34−10−23
Ace-G326.0/150.0−100−34−10−15
Bai-7-G445.0/269.0−120−30−10−19
E1S349.0/269.0−45−52−10−19
E2G447.0/271.0−170−40−10−19
Eze-4’-G584.0/271.0−154−42−10−15
Ica-3-G543.1/367.1−90−33−10−10
Ica-7-G543.1/352.0−90−53−10−10
Lut-3’-G461.2/285.2−87−29−10−15
Que-3-G477.0/301.0−110−32−10−11
Ral-4’-G649.3/473.3−80−44−10−13
Ral-6-G649.3/473.3−80−44−10−13
Scu-7-G461.0/285.0−70−34−10−13
Won-7-G459.0/283.0−87−21−10−15
Rutin (I.S.)609.0/300.0−87−54−10−21
Appendix 4—table 1
Example of fisher exact test generated by the methods described above.
Liver recycling efficiency (%)
HighLow
Intracellular concentrations (nM)High41
Low04
Appendix 4—table 2
The results of Fisher exact test in different weightings were summarized.

p Values of different OATP weightings were calculated and summarized in this table. p<0.05 indicated significant correlation found between recycle ratios and cell uptake. Results marked in red were eliminated.

WeightingpWeightingp
OATP1B1OATP1B3 OATP2B1valueOATP1B1OATP1B3 OATP2B1value
23 50.007971 20.0476
22 60.007970 30.0476
21 70.007982 00.0476
20 80.007980 20.0476
32 50.007981 10.0476
31 60.007991 00.0476
30 70.007990 10.0476
41 50.0079100 00.0476
40 60.0079010 00.1667
51 40.007909 10.1667
50 50.007908 20.1667
60 40.007907 30.1667
03 70.047606 40.1667
02 80.047605 50.1667
01 90.047604 60.1667
00 100.047619 00.1667
13 60.047618 10.1667
12 70.047617 20.1667
11 80.047616 30.1667
10 90.047615 40.1667
33 40.047614 50.1667
44 20.047628 00.1667
43 30.047627 10.1667
42 40.047626 20.1667
54 10.047625 30.1667
53 20.047624 40.1667
52 30.047637 00.1667
64 00.047636 10.1667
63 10.047635 20.1667
62 20.047634 30.1667
61 30.047646 00.1667
73 00.047645 10.1667
72 10.047655 00.1667
Appendix 5—table 1
Peak area of postulated di-glucuronide of luteolin, L3’G, and luteolin from UPLC chromatograph (n = 2).
Retention time/minBefore hydrolysis5 min hydrolysis30 min hydrolysis
Postulated di-glucuronide1.792854326070.518922
L3'G2.6778905.56900642460.5
Luteolin3.02-1728966341
sum107448.5112365.5127723.5

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  1. Yifan Tu
  2. Lu Wang
  3. Yi Rong
  4. Vincent Tam
  5. Taijun Yin
  6. Song Gao
  7. Rashim Singh
  8. Ming Hu
(2021)
Hepatoenteric recycling is a new disposition mechanism for orally administered phenolic drugs and phytochemicals in rats
eLife 10:e58820.
https://doi.org/10.7554/eLife.58820