Effect of quinidine on the dextromethorphan O‐demethylase activity of microsomal fractions from human liver.

Broly, Franck; Libersa, Christian; Lhermitte, Michel; Bechtel, P; Dupuis, B

doi:10.1111/j.1365-2125.1989.tb03502.x

Cited by 57 publications

(37 citation statements)

References 33 publications

(43 reference statements)

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“…All of the TCAs in this study strongly inhibited CYP2D6-catalyzed dextromethorphan O-demethylation. However, quinidine, a CYP2D6-selective inhibitor (Broly et al, 1989), had no effect on phenytoin p-hydroxylation, and cDNA-expressed CYP2D6 failed to produce HPPH, which is consistent with previous reports (Komatsu et al, 2000;Giancarlo et al, 2001). …”

Section: Discussionsupporting

confidence: 82%

“…The inhibitory effects of the TCAs on each P450 isoform were evaluated by human liver microsomal incubations, using probe drugs specific for each P450 isoform. The reaction probes used were phenacetin O-deethylation for CYP1A2 (Tassaneeyakul et al, 1993), S-warfarin 7-hydroxylation for CYP2C9 (Rettie et al, 1992), S-mephenytoin 4Ј-hydroxylation for CYP2C19 (Wrighton et al, 1993), dextromethorphan O-demethylation for CYP2D6 (Broly et al, 1989), and midazolam 1-hydroxylation for CYP3A4 (Thummel et al, 1994). The incubation conditions and analytical assays for the activity of these isoforms were similar to the method previously described (Thummel et al, 1994;Shin et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

“…The inhibitory effects of TCAs and known P450 isoform-selective inhibitors on phenytoin p-hydroxylation were compared to determine the P450 isoform(s) responsible for the interaction between TCAs and phenytoin. The formation rate of HPPH from phenytoin (final concentration, 25 M) was determined from mixtures incubated in the absence or presence of TCAs and known P450 isoformselective inhibitors, furafylline for CYP1A2 (Sesardic et al, 1990), sulfaphenazole for CYP2C9 (Baldwin et al, 1995), omeprazole for CYP2C19 (Ko et al, 1997), quinidine for CYP2D6 (Broly et al, 1989), and ketoconazole for CYP3A4 (Baldwin et al, 1995). Quercetin was tested as a potential inhibitor of CYP2C8 (Desai et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

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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

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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.

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Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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

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“…2), but the reason for this is not known. Values reported for K m for dextromethorphan O-demethylase in liver microsomes range from 2.8 to 22 M (Broly et al, 1989;Dayer et al, 1989;Jacqz-Aigrain et al, 1993;Kerry et al, 1994;Bourrie et al, 1996;Schmider et al, 1996Schmider et al, , 1997Transon et al, 1996;Hickman et al, 1998;Von Moltke et al, 1998;Li et al, 2003) (Fig. 4).…”

Section: Validated Assays For Human Cytochrome P450 Enzymesmentioning

confidence: 99%

Validated Assays for Human Cytochrome P450 Activities

Walsky

Obach²

2004

Drug Metab Dispos

465

380

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ABSTRACT:The measurement of the effect of new chemical entities on human cytochrome P450 marker activities using in vitro experimentation represents an important experimental approach in drug development. In vitro drug interaction data can be used in guiding the design of clinical drug interaction studies, or, when no effect is observed in vitro, the data can be used in place of an in vivo study to claim that no interaction will occur in vivo. To make such a claim, it must be assured that the in vitro experiments are performed with absolute confidence in the methods used and data obtained. To meet this need, 12 semiautomated assays for human P450 marker substrate activities have been developed and validated using approaches described in the GLP (good laboratory practices) as per the code of U.S. Federal Regulations. The assays that were validated are: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), bupropion hydroxylase (CYP2B6), amodiaquine N-deethylase (CYP2C8), diclofenac 4-hydroxylase and tolbutamide methylhydroxylase (CYP2C9), (S)-mephenytoin 4-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1), felodipine dehydrogenase, testosterone 6␤-hydroxylase, and midazolam 1-hydroxylase (CYP3A4 and CYP3A5). High-pressure liquid chromatography-tandem mass spectrometry, using stable isotope-labeled internal standards, has been applied as the analytical method. This analytical approach, through its high sensitivity and selectivity, has permitted the use of very low incubation concentrations of microsomal protein (0.01-0.2 mg/ml). Analytical assay accuracy and precision values were excellent. Enzyme kinetic and inhibition parameters obtained using these methods demonstrated high precision and were within the range of values previously reported in the scientific literature. These methods should prove useful in the routine assessments of the potential for new drug candidates to elicit pharmacokinetic drug interactions via inhibition of cytochrome P450 activities.Drug-drug interactions are of great interest to scientists involved in drug research, regulatory authorities who are responsible for public safety, physicians, and their patients. Since "polypharmacy," or the practice of simultaneous prescription of more than one drug to treat one or more conditions in a single patient, has become a more common practice, drug interactions have been cited as one of the major reasons for hospitalization and even death (Lazarou et al., 1998). Thus, a great deal of effort is expended by researchers engaged in new drug research in avoiding the development of compounds that will cause drug-drug interactions.The most common mechanism underlying drug-drug interactions is the inhibition of cytochrome P450 activities. Several drugs in common use cause large increases in exposure to other drugs. Examples include ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, and nefazodone (CYP3A); quinidine, paroxetine, and terbinafine (CYP2D6); ticlopidine (CYP2C19); ...

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“…Selective CYP inhibitors were used in this study to validate that the assays were working properly. 7,8-Benzoflavone, 17) furafylline, 18) orphenadrine, 19) quercetin, 20) sulfaphenazole, 21) tranylcypromine, 22) quinidine, 23) diethyldithiocarbamate, 24) and ketoconazole, 25) which are inhibitors of CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 activities, respectively, inhibited the respective enzyme activities (data not shown). Diethyldithiocarbamate is also known to be a specific inhibitor of CYP2A6, 17) and the present study confirmed the potent inhibitory capability of this compound on CYP2A6-mediated metabolism (data not shown).…”

Section: Chemicalsmentioning

confidence: 99%