Different effects of inhibitors on the O  - and N  -demethylation of codeine in human liver microsomes

Qy, Yue; Säwe, Juliette

doi:10.1007/s002280050247

Cited by 42 publications

(19 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Codeine, whose backbone chemical structure is strikingly similar to that of dextromethorphan, is metabolized to morphine and norcodeine through O-and N-demethylation, respectively. In humans, codeine O-and N-demethylation are attributable to isoforms CYP2D6 and CYP3A, respectively (Caraco et al, 1996;Yue and Sawe, 1997). In our previous study on CYP2D6 pharmacogenetics, we found that all the CYP2D6 allelic variants catalyzed primarily codeine O-demethylation (Yu et al, 2002).…”

Section: Characterization Of Mouse Cyp2d22mentioning

confidence: 75%

Expression, Purification, and Characterization of Mouse Cyp2d22

Yu¹,

Haining²

2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Metabolism of the prototype human CYP2D6 substrates debrisoquine and bufuralol proceeds at a much slower rate in mice; therefore, the mouse has been proposed as an animal model for the human CYP2D6 genetic deficiency. To interpret the molecular mechanism of this deficiency, a cDNA belonging to the CYP2D gene subfamily (Cyp2d22) has been cloned and sequenced from a mouse mammary tumor-derived cell line. In the current study, Cyp2d22 enzyme was overexpressed and purified from insect cells using a baculovirus-mediated system. The activity of this purified enzyme was directly compared with purified human CYP2D6 toward codeine, dextromethorphan, and methadone as substrates. Purified Cyp2d22 was found to catalyze the O-demethylation of dextromethorphan with significantly higher K m values (250 M) than that (4.2 M) exhibited by purified human CYP2D6. The K m for dextromethorphan N-demethylation by Cyp2d22 was found to be 418 M, much lower than that observed with human CYP2D6 and near the K m for dextromethorphan N-demethylation catalyzed by CYP3A4. CYP2D6 catalyzed codeine O-demethylation, whereas Cyp2d22 and CYP3A4 mediated codeine N-demethylation. Furthermore, methadone, a known CYP3A4 substrate and CYP2D6 inhibitor, was N-demethylated by Cyp2d22 with a K m of 517 M and V max of 4.9 pmol/pmol/min. Quinidine and ketoconazole, potent inhibitors to CYP2D6 and CYP3A4, respectively, did not show strong inhibition toward Cyp2d22-mediated dextromethorphan Oor N-demethylation. These results suggest that mouse Cyp2d22 has its own substrate specificity beyond CYP2D6-like-deficient activity.

show abstract

Section: Characterization Of Mouse Cyp2d22mentioning

confidence: 75%

Expression, Purification, and Characterization of Mouse Cyp2d22

Yu¹,

Haining²

2006

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…However, there is some evidence on their moderate to high inhibitory potential on CYP 2C19 and CYP 2D6 isoenzymes [29,30] . Much more information is available about SSRIs.…”

Section: Interactions Between Ads and Cytostaticsmentioning

confidence: 99%

“…The same occurs with the other ANs in the antimicrotubules category (vinblastine, vincristine, vindesine, vinorelbine), corticosteroids, etoposide, irinotecan and sorafenib whose overlap use with CYP 3A4 inhibitors can increase toxicity, and with CYP 3A4 inducers reduce efficacy [36] . In the case of exemestane and letrozole, the likely toxicity with the use of CYP 3A4 inhibitors is translated into myalgia, constitutional symptoms, peripheral edema and hot flushes [29] . Under these conditions, regarding imatinib, the most prominent adverse symptoms are the weight gain, nausea, vomiting and neutropenia [36] .…”

Section: Interactions Between Ads and Cytostaticsmentioning

confidence: 99%

“…Procarbazine is subject, to a lesser extent, to metabolization in CYP 1A [36] with the formation of ActiveMet; therefore, using this isoenzyme's inhibitors (e.g. fluvoxamine [14] ) can also reduce the effectiveness of this AN [29] . The same applies to dacarbazine whose route of biotransformation matches that of procarbazine [36] .…”

Section: Interactions Between Ads and Cytostaticsmentioning

confidence: 99%

See 1 more Smart Citation

Drug Interaction in Psycho-Oncology: Antidepressants and Antineoplastics

Miguel

Albuquerque

2011

Pharmacology

View full text Add to dashboard Cite

Background and Objectives: Although there is a growing impact of psychiatric and depressive disorders in cancer patients, literature on the idiosyncrasies of antidepressants (ADs) used in those conditions and their interactions with antineoplastic agents (ANs) is scarce. Sharing the same biotransformation pathways enhances the risk of drug interaction between ADs and ANs, specifically when compounds are inducers, inhibitors or substrates of cytochrome P450 (CYP 450). In cancer patients, such drug interactions may result in less efficacy of the drug and/or increase of their side effects. Therefore, the choice of AD should be cautious (safe and effective) and well supported. The main purpose of this review was to analyze the individual pharmacokinetic properties of the most used ADs and ANs in order to summarize the risk of possible drug interactions between them, anticipating the consequences of their coadministration. Methods: The authors reviewed books and PubMed online articles published in the last 6 years. Results: Most of the ANs are subject to transformation by CYP 450 3A4 and their coadministration with ADs, that have inhibitory properties of this CYP isoform, such as fluoxetine, sertraline, paroxetine and fluvoxamine, may result in the loss of the AN’s efficacy or higher toxicity. Conclusion: Among the ADs, escitalopram, citalopram, venlafaxine, mirtazapine and milnacipran stand out for their weak CYP 450 inhibitory potential and their safety profile in those patients.

show abstract

“…Except for one report of moderate inhibition of CYP2D6-catalyzed codeine O-demethylation (Yue and Säwe, 1997), however, the inhibitory potential of TCAs on different P450 isoforms has not been extensively described. Our study demonstrated strong inhibition of CYP2D6-catalyzed dextromethorphan O-demethylation by all of the TCAs examined; estimated K i values of the TCAs were ranked as follows: amitriptyline (31.0 M) Ͼ imipramine (28.6 M) Ͼ desipramine (12.5 M) Ͼ nortriptyline (7.9 M).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin

Shin¹,

Park²,

Kim³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The ability of tricyclic antidepressants (TCAs) to inhibit phenytoin p-hydroxylation was evaluated in vitro by incubation studies of human liver microsomes and cDNA-expressed cytochrome P450s (P450s). The TCAs tested were amitriptyline, imipramine, nortriptyline, and desipramine. Amitriptyline and imipramine strongly and competitively inhibited phenytoin p-hydroxylation in microsomal incubations (estimated K i values of 5.2 and 15.5 M, respectively). In contrast, nortriptyline and desipramine produced only weak inhibition. In the incubation study using cDNA-expressed P450s, both CYP2C9 and CYP2C19 catalyzed phenytoin p-hydroxylation, whereas TCAs inhibited only the CYP2C19 pathway. All of the TCAs tested inhibited CYP2D6-catalyzed dextromethorphan-O-demethylation competitively, with estimated K i values of 31.0, 28.6, 7.9, and 12.5 M, respectively. The tertiary amine TCAs, amitriptyline and imipramine, also inhibited CYP2C19-catalyzed S-mephenytoin 4-hydroxylation (estimated K i of 37.7 and 56.8 M, respectively). The secondary amine TCAs, nortriptyline and desipramine, however, showed minimal inhibition of CYP2C19 (estimated IC 50 of 600 and 685 M, respectively). None of the TCAs tested produced remarkable inhibition of any other P450 isoforms. These results suggest that TCAs inhibit both CYP2D6 and CYP2C19 and that the interaction between TCAs and phenytoin involves inhibition of CYP2C19-catalyzed phenytoin p-hydroxylation.

show abstract

Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes

Cited by 42 publications

References 46 publications

Expression, Purification, and Characterization of Mouse Cyp2d22

Expression, Purification, and Characterization of Mouse Cyp2d22

Drug Interaction in Psycho-Oncology: Antidepressants and Antineoplastics

Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin

Contact Info

Product

Resources

About