Quantitation of CYP2B6, Constitutive Androstane Receptor, and Pregnane X Receptor mRNA levels

Hesse, Leah M.; Court, Michael H.

doi:10.1124/dmd.31.5.685

Cited by 6 publications

(11 citation statements)

References 6 publications

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“…In addition, bupropion showed inhibition of S ‐mephenytoin 4′‐hydroxylation, and dextromethorphan O ‐demethylation (data not shown). This observation is consistent with the in vitro drug interaction study of bupropion conducted by Hesse et al .,13 which showed that bupropion inhibits CYP2D6‐catalyzed dextromethorphan O ‐demethylation (IC 50 = 58 µM). In our methodology, therefore, two sets of cocktail doses were separated in the microsomal incubation step.…”

Section: Resultssupporting

confidence: 91%

“…4). The IC 50 values determined with each cocktail set using this methodology were comparable to those obtained from the incubations of individual substrates in the present study (Table 4) and with literature values 7, 9, 10, 13, 22, 27, 32–41. This demonstrates that the IC 50 values of P450 inhibitors can be accurately determined using the cocktail incubation approach instead of nine separate individual substrate incubations, which saves a tremendous amount of time in the P450 inhibition screening process for new chemical entities.…”

Section: Resultssupporting

confidence: 87%

“…This approach has allowed the rapid and simple assessment of the potential inhibitory effect of test compounds on P450 enzymes, but the methods reported were developed for the screening of only six major human hepatic P450s, namely, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. However, recent studies have discussed the clinical significance of CYP2A6,11, 12 CYP2B6,13, 14 and CYP2C8,15–17 in addition to the six major P450 enzymes, with respect to drug interactions. For example, the anticancer drug thioTEPA was shown to cause a significant decrease in the plasma levels of the active cyclophosphamide metabolite by inhibiting CYP2B6 activity 14.…”

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confidence: 99%

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High‐throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography/tandem mass spectrometry

Kim

Cha

et al. 2005

Rapid Comm Mass Spectrometry

152

142

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The early detection of potential drug-drug interactions is an important issue of drug discovery that has led to the development of high-throughput screening (HTS) methods for potential drug interactions. We developed a HTS method for potential interactions of inhibitory drugs for nine human P450 enzymes using cocktail incubation and tandem mass spectrometry in vitro. This new method involves incubation of two cocktail doses and single cassette analysis. The two cocktail doses in vitro were developed to minimize solvent effects and mutual drug interactions among substrates: cocktail A was composed of phenacetin for CYP1A2, coumarin for CYP2A6, paclitaxel for CYP2C8, S-mephenytoin for CYP2C19, dextromethorphan for CYP2D6, and midazolam for CYP3A4; and cocktail B was composed of three substrates including bupropion for CYP2B6, tolbutamide for CYP2C9, and chlorzoxazone for CYP2E1. In the incubation study of these cocktails, the reaction mixtures were pooled and simultaneously analyzed using liquid chromatography/tandem mass spectrometry employing a fast gradient. The method was validated by comparing the inhibition data obtained from the incubation of each individual probe substrate alone with data from the new method. The IC50 value of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values previously reported in the literature. As a HTS method for potential interactions of the inhibition of these nine P450 enzymes, this new method will be useful in the drug discovery process and for the mechanistic understanding of drug interactions.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 87%

mentioning

confidence: 99%

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High‐throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography/tandem mass spectrometry

Kim

Cha

et al. 2005

Rapid Comm Mass Spectrometry

152

142

View full text Add to dashboard Cite

show abstract

“…[15][16][17] The CYP2D6 inhibitory effect caused by BUP in vivo is more pronounced than what could be explained by initial in vitro experiments. 5,18 Later studies report that both BUP and its metabolites inhibit CYP2D6 through competitive, reversible inhibition. 19,20 The metabolites have higher CYP2D6 inhibition potency than BUP, ranged as following: erythrohydro-BUP > threohydro-BUP > OHBUP > BUP, with K i = 1.7, 5.4, 13, and 21 μM, respectively.…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression

Hole

Arnestad

Molden

et al. 2021

J Clin Psychopharmacol

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PurposeThe aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression.MethodsPatients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included.FindingsA total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater.ConclusionsBupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.

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“…Question 3 (Table 2): Hydroxybupropion was produced from 5 × 10 −5 M bupropion by cytochrome P450 2B6, which suggests that bupropion is a substrate for cytochrome P450 2B6. 6 Oral contraceptive (ethinyl estradiol and desogestrel) reduced the area under the concentration–time curves of hydroxybupropion (metabolite of bupropion by cytochrome P450 2B6) 4 (Score: 1). Question 4 (Table 2): unknown (Score: 0).…”

mentioning

confidence: 99%

Drug Interaction Probability Assessment

Sohn

2021

American Journal of Therapeutics

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Quantitation of CYP2B6, Constitutive Androstane Receptor, and Pregnane X Receptor mRNA levels

Abstract: 1 Abbreviations used are: CAR, constitutive androstane receptor; PXR, pregnane X receptor; HNF-1␣, hepatocyte nuclear factor-1␣; UGT, UDP-glucuronosyltransferase.0090-9556/03/3105-685$7.00

Cited by 6 publications

References 6 publications

High‐throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography/tandem mass spectrometry

High‐throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography/tandem mass spectrometry

Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression

Drug Interaction Probability Assessment

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