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Effects of mitragynine and 7-hydroxymitragynine (the alkaloids of Mitragyna speciosa Korth) on 4-methylumbelliferone glucuronidation in rat and human liver microsomes and recombinant human uridine 5'-diphospho-glucuronosyltransferase isoforms.

Haron M, Ismail S - Pharmacognosy Res (2014 Oct-Dec)

Bottom Line: For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM.For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM.These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity.

View Article: PubMed Central - PubMed

Affiliation: Centre for Drug Research, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.

ABSTRACT

Background: Glucuronidation catalyzed by uridine 5'- diphospho-glucuronosyltransferase (UGT) is a major phase II drug metabolism reaction which facilitates drug elimination. Inhibition of UGT activity can cause drug-drug interaction. Therefore, it is important to determine the inhibitory potentials of drugs on glucuronidation.

Objective: The objective was to evaluate the inhibitory potentials of mitragynine, 7-hydroxymitragynine, ketamine and buprenorphine, respectively on 4-methylumbelliferone (4-MU) glucuronidation in rat liver microsomes, human liver microsomes and recombinant human UGT1A1 and UGT2B7 isoforms.

Materials and methods: The effects of the above four compounds on the formation of 4-MU glucuronide from 4-MU by rat liver microsomes, human liver microsomes, recombinant human UGT1A1 and UGT2B7 isoforms were determined using high-performance liquid chromatography with ultraviolet detection.

Results: For rat liver microsomes, ketamine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.21 ± 1.51 μM followed by buprenorphine with an IC50 value of 73.22 ± 1.63 μM. For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM. For human UGT1A1 isoform, 7-hydroxymitragynine strongly inhibited 4-MU glucuronidation with an IC50 value of 7.13 ± 1.16 μM. For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM.

Conclusions: These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity. In addition, if 7-hydroxymitragynine is to be taken with other drugs that are highly metabolized by UGT1A1, there is a possibility of drug-drug interaction to occur.

No MeSH data available.


Inhibitory effects of mitragynine, 7-hydroxymitragynine, ketamine, buprenorphine, and diclofenac on 4-methylumbelliferone glucuronide formation by human liver microsomes. Panels to the right show inhibitor concentrations. Each bar represents the mean percentage activity relative to control ± standard error of mean for three independent measurements (n = 3). Statistical analysis was conducted using one-way ANOVA and Dunnett test. *P < 0.05 versus control (no inhibitor)
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Figure 3: Inhibitory effects of mitragynine, 7-hydroxymitragynine, ketamine, buprenorphine, and diclofenac on 4-methylumbelliferone glucuronide formation by human liver microsomes. Panels to the right show inhibitor concentrations. Each bar represents the mean percentage activity relative to control ± standard error of mean for three independent measurements (n = 3). Statistical analysis was conducted using one-way ANOVA and Dunnett test. *P < 0.05 versus control (no inhibitor)

Mentions: Using human liver microsomes, diclofenac showed inhibition with IC50 value of 86.44 ± 1.28 μM [mean ± SEM, Table 1]. Buprenorphine showed inhibition with IC50 value of 6.32 ± 1.39 μM [mean ± SEM, Table 1]. The percentage inhibition of UGT activity is varied from 16% ± 3% to 33% ± 4% for mitragynine, 8% ± 3% to 32% ± 1% for ketamine and 5% ± 1% to 17% ± 1% for 7-hydroxymitragynine at concentrations that ranged from 0.01 to 1000 μM for ketamine whereas 0.01 to 100 μM for mitragynine and 7-hydroxymitragynine [Figure 3]. The IC50 values for these three compounds toward 4-MU glucuronidation in human liver microsomes were all greater than the highest concentrations used (IC50 > 1000 μM for ketamine whereas IC50 > 100 μM for mitragynine and 7-hydroxymitragynine) since inhibition at more than 50% did not occur at the highest concentration [Table 1].


Effects of mitragynine and 7-hydroxymitragynine (the alkaloids of Mitragyna speciosa Korth) on 4-methylumbelliferone glucuronidation in rat and human liver microsomes and recombinant human uridine 5'-diphospho-glucuronosyltransferase isoforms.

Haron M, Ismail S - Pharmacognosy Res (2014 Oct-Dec)

Inhibitory effects of mitragynine, 7-hydroxymitragynine, ketamine, buprenorphine, and diclofenac on 4-methylumbelliferone glucuronide formation by human liver microsomes. Panels to the right show inhibitor concentrations. Each bar represents the mean percentage activity relative to control ± standard error of mean for three independent measurements (n = 3). Statistical analysis was conducted using one-way ANOVA and Dunnett test. *P < 0.05 versus control (no inhibitor)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660513&req=5

Figure 3: Inhibitory effects of mitragynine, 7-hydroxymitragynine, ketamine, buprenorphine, and diclofenac on 4-methylumbelliferone glucuronide formation by human liver microsomes. Panels to the right show inhibitor concentrations. Each bar represents the mean percentage activity relative to control ± standard error of mean for three independent measurements (n = 3). Statistical analysis was conducted using one-way ANOVA and Dunnett test. *P < 0.05 versus control (no inhibitor)
Mentions: Using human liver microsomes, diclofenac showed inhibition with IC50 value of 86.44 ± 1.28 μM [mean ± SEM, Table 1]. Buprenorphine showed inhibition with IC50 value of 6.32 ± 1.39 μM [mean ± SEM, Table 1]. The percentage inhibition of UGT activity is varied from 16% ± 3% to 33% ± 4% for mitragynine, 8% ± 3% to 32% ± 1% for ketamine and 5% ± 1% to 17% ± 1% for 7-hydroxymitragynine at concentrations that ranged from 0.01 to 1000 μM for ketamine whereas 0.01 to 100 μM for mitragynine and 7-hydroxymitragynine [Figure 3]. The IC50 values for these three compounds toward 4-MU glucuronidation in human liver microsomes were all greater than the highest concentrations used (IC50 > 1000 μM for ketamine whereas IC50 > 100 μM for mitragynine and 7-hydroxymitragynine) since inhibition at more than 50% did not occur at the highest concentration [Table 1].

Bottom Line: For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM.For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM.These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity.

View Article: PubMed Central - PubMed

Affiliation: Centre for Drug Research, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.

ABSTRACT

Background: Glucuronidation catalyzed by uridine 5'- diphospho-glucuronosyltransferase (UGT) is a major phase II drug metabolism reaction which facilitates drug elimination. Inhibition of UGT activity can cause drug-drug interaction. Therefore, it is important to determine the inhibitory potentials of drugs on glucuronidation.

Objective: The objective was to evaluate the inhibitory potentials of mitragynine, 7-hydroxymitragynine, ketamine and buprenorphine, respectively on 4-methylumbelliferone (4-MU) glucuronidation in rat liver microsomes, human liver microsomes and recombinant human UGT1A1 and UGT2B7 isoforms.

Materials and methods: The effects of the above four compounds on the formation of 4-MU glucuronide from 4-MU by rat liver microsomes, human liver microsomes, recombinant human UGT1A1 and UGT2B7 isoforms were determined using high-performance liquid chromatography with ultraviolet detection.

Results: For rat liver microsomes, ketamine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.21 ± 1.51 μM followed by buprenorphine with an IC50 value of 73.22 ± 1.63 μM. For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM. For human UGT1A1 isoform, 7-hydroxymitragynine strongly inhibited 4-MU glucuronidation with an IC50 value of 7.13 ± 1.16 μM. For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM.

Conclusions: These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity. In addition, if 7-hydroxymitragynine is to be taken with other drugs that are highly metabolized by UGT1A1, there is a possibility of drug-drug interaction to occur.

No MeSH data available.