Inhibition of Udp-Glucuronosyltransferase 2b7-Catalyzed Morphine Glucuronidation by Ketoconazole: Dual Mechanisms Involving a Novel Noncompetitive Mode

Takeda, Shuso; Kitajima, Yurie; Ishii, Yuji; Nishimura, Yoshio; Mackenzie, Peter I.; Oguri, Kazuta; Yamada, Hideyuki

doi:10.1124/dmd.106.009738

Cited by 61 publications

(53 citation statements)

References 31 publications

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“…4B) of pitavastatin glucuronidation. This is consistent with ketoconazole not being a potent inhibitor of OATP1B, UGT1A3, or UGT2B7 at the concentration tested (2 mM) (Takeda et al, 2006). These results suggest that the observed inhibition of pitavastatin glucuronidation by BOC, telaprevir and rifampin (in increasing order) is likely a consequence of their inhibition of the OATP1B-mediated hepatic uptake rather than direct inhibition of UGT-mediated glucuronidation.…”

supporting

confidence: 74%

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldoketoreductases, was a reversible time-dependent inhibitor (k inact = 0.12 minute 21, K I = 6.1 mM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC 50 of 18 and 4.9 mM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.

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confidence: 74%

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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“…Although the triazole itraconazole was without effect on UGT2B10, the imidazole ketoconazole was a relatively potent inhibitor of this enzyme (IC 50 = 11.9 6 1.7 mM). Similar to the inhibition selectivity of fluconazole, ketoconazole has previously been reported to be a relatively potent inhibitor of UGT2B4 (Raungrut et al, 2010) and an inhibitor of UGT2B7 (Takeda et al, 2006).…”

Section: Discussionmentioning

confidence: 96%

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

Pattanawongsa

Nair

Rowland

et al. 2015

Drug Metabolism and Disposition

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Although there is evidence for an important role of UGT2B10 in the N-glucuronidation of drugs and other xenobiotics, the inhibitor selectivity of this enzyme is poorly understood. This study sought primarily to characterize the inhibition selectivity of UGT2B10 by UDP-glucuronosyltransferase (UGT) enzyme-selective inhibitors used for reaction phenotyping, and 34 antidepressant and antipsychotic drugs that contain an amine functional group. Initial studies demonstrated that cotinine is a highly selective substrate of human liver microsomal UGT2B10. The kinetics of cotinine N-glucuronidation by recombinant UGT and human liver microsomes (6 bovine serum albumin) were consistent with the involvement of a single enzyme. Of the UGT enzyme-selective inhibitors employed for reaction phenotyping, only the UGT2B4/7 inhibitor fluconazole reduced recombinant UGT2B10 activity to an appreciable extent. The majority of antidepressant and antipsychotic drugs screened for effects on UGT2B10 inhibited enzyme activity with IC 50 values <100 mM. The most potent inhibition was observed with the tricyclic antidepressants amitriptyline and doxepin and the tetracyclic antidepressant mianserin, and the structurally related compounds desloratadine and loratadine. Molecular modeling using a ligand-based approach indicated that hydrophobic and charge interactions are involved in inhibitor binding, whereas spatial features influence the potency of UGT2B10 inhibition. Respective mean K i,u (6 S.D.) values for amitriptyline, doxepin, and mianserin inhibition of human liver microsomal UGT2B10 were 0.61 6 0.05, 0.95 6 0.18, and 0.43 6 0.01 mM. In vitro-in vivo extrapolation indicates that these drugs may perpetrate inhibitory drug-drug interactions when coadministered with compounds that are cleared predominantly by UGT2B10.

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“…Immunoprecipitation of CYP3A4 from human liver microsomes resulted in co-immunoprecipitation of UGT2B7, UGT1A1, and UGT1A6 (40). The functional rele-vance of CYP-UGT interaction was tested by co-expressing CYP3A4 and UGT2B7 in COS cells, and it was found that UGT2B7-catalyzed glucuronidation of morphine was altered by the presence of CYP3A4 (41). Studies have also indicated that baculovirus-expressed cytochrome P450 catalytic activity may be altered by the co-expression of different cytochrome P450s (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Oligomerization of the UDP-glucuronosyltransferase 1A Proteins

Operaña

Tukey

2007

Journal of Biological Chemistry

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UDP-glucuronosyltransferases (UGTs) are membrane-bound proteins localized to the endoplasmic reticulum and catalyze the formation of ␤-D-glucopyranosiduronic acids (glucuronides) using UDP-glucuronic acid and acceptor substrates such as drugs, steroids, bile acids, xenobiotics, and dietary nutrients. Recent biochemical evidence indicates that the UGT proteins may oligomerize in the membrane, but conclusive evidence is still lacking. In the present study, we have used fluorescence resonance energy transfer (FRET) to study UGT1A oligomerization in live cells. This technique demonstrated that UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10 self-oligomerize (homodimerize). Heterodimer interactions were also explored, and it was determined that UGT1A1 was capable of binding with UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10. In addition to the in vivo FRET analysis, UGT1A protein-protein interactions were demonstrated through co-immunoprecipitation experiments. Co-expression of hemagglutinin-tagged and cyan fluorescent protein-tagged UGT1A proteins, followed by immunoprecipitation with anti-hemagglutinin beads, illustrated the potential of each UGT1A protein to homodimerize. Co-immunoprecipitation results also confirmed that UGT1A1 was capable of forming heterodimer complexes with all of the UGT1A proteins, corroborating the FRET results in live cells. These preliminary studies suggest that the UGT1A family of proteins form oligomerized complexes in the membrane, a property that may influence function and substrate selectivity.

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Inhibition of Udp-Glucuronosyltransferase 2b7-Catalyzed Morphine Glucuronidation by Ketoconazole: Dual Mechanisms Involving a Novel Noncompetitive Mode

Cited by 61 publications

References 31 publications

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

Oligomerization of the UDP-glucuronosyltransferase 1A Proteins

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