zidovudine
Inhibition of UGT2B7 Enzyme Activity in Human and Rat Liver Microsomes by Herbal Constituents CSV JSON

The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (Vmax/Km) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC50 values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC50 values of 51.20 ± 5.95 µM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans.

zidovudine

30347696

623736757

1 . Zidovudine Glucoridination Kinetics in Human Liver Microsomes Without BSA (id=NPDI-xu0IJQ)

In Vitro Enzyme Kinetics Experiment

Metabolism was detected.

zidovudine

zidovudine glucuronide

  • UGT2B7

Cell fraction Pooled human liver microsomes -7999662

Results

Table 4 - HLM Without 1% BSA

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Without 1% bovine serum albumin (BSA)

Metabolite formation study

0.5 mg/mL

In-house preparation

120 min

Available

Available

0 - 6 mM

2 . Zidovudine Glucoridination Kinetics in Rat Liver Microsomes With BSA (id=NPDI-msAUiw)

In Vitro Enzyme Kinetics Experiment

Metabolism was detected.

zidovudine

zidovudine glucuronide

  • UGT2B7

Cell fraction Rat liver microsomes

Results

Table 4 - RLM With 1% BSA

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

With 1% bovine serum albumin (BSA)

Metabolite formation study

6 mg/mL

In-house preparation

90 min

Available

Available

0 - 6 mM

3 . Zidovudine Glucoridination Kinetics in Rat Liver Microsomes Without BSA (id=NPDI-dNsfLA)

In Vitro Enzyme Kinetics Experiment

Metabolism was detected.

zidovudine

zidovudine glucuronide

  • UGT2B7

Cell fraction Rat liver microsomes

Results

Table 4 - RLM Without 1% BSA

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Without 1% bovine serum albumin (BSA)

Metabolite formation study

6 mg/mL

In-house preparation

90 min

Available

Available

0 - 6 mM

4 . Zidovudine Glucoridination Kinetics in Human Liver Microsomes With BSA (id=NPDI-7o9w1Q)

In Vitro Enzyme Kinetics Experiment

Metabolism was detected.

zidovudine

zidovudine glucuronide

  • UGT2B7

Cell fraction Pooled human liver microsomes -7999662

Results

Table 4 - HLM With 1% BSA

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

With 1% bovine serum albumin (BSA)

Metabolite formation study

0.5 mg/mL

In-house preparation

120 min

Available

Available

0 - 6 mM

1 . Inhibition of Mitragynine on ZDV Glucoronidation in RLM (id=NPDI-C7Expw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

50% inhibition at concentration below 100 µM

zidovudine

mitragynine

zidovudine glucuronide

  • UGT2B7

Cell fraction Rat liver microsomes

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

1, 10, 100 µM

2 . Inhibition of Mitragynine on ZDV Glucoronidation in HLM (id=NPDI-Az8-Ow)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

50% inhibition at concentration below 100 µM

zidovudine

mitragynine

zidovudine glucuronide

  • UGT2B7

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

1, 10, 100 µM