Interactions of Olomoucine II with Human Liver Microsomal Cytochromes P450

Siller, Michal; Anzenbacher, Pavel; Anzenbacherová, Eva; Doležal, Karel; Popa, Igor; Strnad, Miroslav

doi:10.1124/dmd.108.025502

Cited by 9 publications

(6 citation statements)

References 22 publications

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“…Olomoucine II, a cyclindependent kinase inhibitor used as a potential antineoplastic agent, significantly inhibited CYP2C9 with an IC 50 of 39.1 M in vitro [1412]. Dalcetrapib inhibited CYP2C9 moderately in vitro, but it did not alter the activity of CYP2C9 in vivo [1413].…”

Section: Other Drugs and Compoundsmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Other Drugs and Compoundsmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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“…A recent study of Olomoucine II in vitro P450 metabolism reveals a potential hydroxylated metabolite with m/z 387 (the same m/z as product 1d), which has been identified as 2,5-dihydroxyroscovitine [51]. However, as shown above, comparison with a synthetic standard failed to reveal the product occurence in the EC cell.…”

Section: Comparison With Previous In Vitro Experimentsmentioning

confidence: 83%

High Performance Liquid Chromatography‐Electrochemistry‐Electrospray Ionization Mass Spectrometry (HPLC/EC/ESI‐MS) for Detection and Characterization of Roscovitine Oxidation Products

Karády¹,

Novák²,

Horna³

et al. 2011

Electroanalysis

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On-line LC-EC/ESI-MS has been established as a fast and simple method to mimic some types of oxidation reaction of various drugs and to study the formation and structure of the resulting products. This technique has been applied to a 2,6,9-trisubstituted purine, R-roscovitine, which is known to be an inhibitor of some cyclin-dependent kinases (CDKs) and a potential anticancer drug. Oxidation of R-roscovitine in an electrochemical cell (EC), operated under various conditions, resulted in appearance of 6 major products. These were further analyzed by high-resolution mass spectrometry, their structures were elucidated by accurate mass measurement and compared to previously identified R-roscovitine in vitro/in vivo metabolites. Although none of the observed products was structurally identical to those identified previously in vitro/in vivo, all of them, except for the methoxylated products, resembled similarity due to appearing through the same reaction type. R-roscovitine in the EC cell underwent N-dealkylation of the isopropyl moiety, hydroxylation of the aromatic side-chain, dihydroxylation, methoxylation and dimer formation. The hydroxylation product was identified as Olomoucine II, a R-roscovitine derivative, which displays 10-times higher CDK-inhibiting activity than R-roscovitine and the occurrence of which, as R-roscovitine product, has not yet been observed in vitro/in vivo.

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“…The protein concentrations and incubation times for rosiglitazone metabolism in the microsomes were optimized to ensure that the metabolism of rosiglitazone at the incubation times and protein concentrations used in the final experiment followed first-order kinetics. Rosiglitazone metabolism in human liver microsomes (Table 1 ) was performed in the incubation media using sodium phosphate buffer (100 mM, pH 7.4), with a final volume of 100 μL containing: 40 μg microsomal protein in 50 μL of buffer (equal to 0.4 mg/mL), 25 μL of the NADPH-generating system (including 7 mM NADP, 1.25 units isocitric acid dehydrogenase, 18 mM isocitric acid, and 20 mM magnesium chloride) [ 9 ], and 25 μL rosiglitazone (at required concentrations). Incubations were performed at 37 °C in a shaking water bath for 0–25 min, with sampling times of 0, 5, 7.5, 10, 15, 20, and 25 min.…”

Section: Methodsmentioning

confidence: 99%

Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method

et al. 2017

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BackgroundElimination of rosiglitazone in humans is via hepatic metabolism. The existing studies suggest that CYP2C8 is the major enzyme responsible, with a minor contribution from CYP2C9; however, other studies suggest the involvement of additional cytochrome P450 enzymes and metabolic pathways. Thus a full picture of rosiglitazone metabolism is unclear.ObjectiveThis study aimed to improve the current understanding of potential drug–drug interactions and implications for therapy by evaluating the kinetics of rosiglitazone metabolism and examining the impact of specific inhibitors on its metabolism using the substrate depletion method.MethodsIn vitro oxidative metabolism of rosiglitazone in human liver microsomes obtained from five donors was determined over a 0.5–500 µM substrate range including the contribution of CYP2C8, CYP2C9, CYP3A4, CYP2E1, and CYP2D6.ResultsThe maximum reaction velocity was 1.64 ± 0.98 nmol·mg−1·min−1. The CYP2C8 (69 ± 20%), CYP2C9 (42 ± 10%), CYP3A4 (52 ± 23%), and CEP2E1 (41 ± 13%) inhibitors all significantly inhibited rosiglitazone metabolism.ConclusionThe results suggest that other cytochrome P450 enzymes, including CYP2C9, CYP3A4, and CEP2E1, in addition to CYP28, also play an important role in the metabolism of rosiglitazone. This example demonstrates that understanding the complete metabolism of a drug is important when evaluating the potential for drug–drug interactions and will assist to improve the current therapeutic strategies.

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Interactions of Olomoucine II with Human Liver Microsomal Cytochromes P450

Cited by 9 publications

References 22 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

High Performance Liquid Chromatography‐Electrochemistry‐Electrospray Ionization Mass Spectrometry (HPLC/EC/ESI‐MS) for Detection and Characterization of Roscovitine Oxidation Products

Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method

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