zidovudine
Inhibition of UGT2B7 Enzyme Activity in Human and Rat Liver Microsomes by Herbal Constituents
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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.
1 . 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
- 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
2 . 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
- UGT2B7
Cell fraction Rat liver microsomes
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
1, 10, 100 µM
1 . Zidovudine Glucoridination Kinetics in Human Liver Microsomes With BSA (id=NPDI-7o9w1Q)
In Vitro Enzyme Kinetics Experiment
Metabolism was detected.
- 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
2 . Zidovudine Glucoridination Kinetics in Rat Liver Microsomes Without BSA (id=NPDI-dNsfLA)
In Vitro Enzyme Kinetics Experiment
Metabolism was detected.
- 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
3 . Zidovudine Glucoridination Kinetics in Rat Liver Microsomes With BSA (id=NPDI-msAUiw)
In Vitro Enzyme Kinetics Experiment
Metabolism was detected.
- 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
4 . Zidovudine Glucoridination Kinetics in Human Liver Microsomes Without BSA (id=NPDI-xu0IJQ)
In Vitro Enzyme Kinetics Experiment
Metabolism was detected.
- 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