Can the CEIBA Cocktail Designed for Human Cytochrome P450 Enzymes be Used in the Rat for Drug Interaction Studies?

Purpose - The CEIBA cocktail consisting of caffeine (CAF), omeprazole (OZ), dextromethorphan (DM) and losartan (LOS) was previously proposed for the clinical phenotyping of five major human cytochrome P450 (CYP) isoenzymes. This work aimed to assess the usefulness of CEIBA cocktail to study non-clinical drug interactions in the rat. Methods - Wistar rats were divided into five groups to receive a single-oral dose of each probe drug (CAF, OZ, LOS, DM), individually or in combination as a cocktail. Plasma concentrations of the probe drugs and their metabolites [paraxanthine (1,7-X), 5-hydroxyomeprazole (5-OZ), losartan carboxylic acid (E-3174), dextrorphan (DX) and 3-methoxymorphinan (3-MM)] were determined by LC-MS/MS, and the corresponding pharmacokinetic parameters were estimated by non-compartmental analysis. The AUC0-t and Cmax drug/metabolite ratios (phenotypic metrics) were calculated for each probe drug and compared (probe alone versus cocktail). Results - The primary analysis of the pharmacokinetic data suggested the occurrence of pharmacokinetic-based drug interactions when the probe drugs were concurrently administered; such interactions were documented for CAF, 1,7-X, DX and E-3174. Nevertheless, except for the LOS/E-3174 probe drug-metabolite pair (p<0.05), there was little evidence that the probe drugs interacted metabolically as the metabolic ratios calculated were similar in both approaches. Moreover, no evidence was found for relevant pharmacodynamic interactions. Conclusion - CEIBA cocktail seems to be a useful tool to investigate drug interactions involving CYP isoenzymes in the rat, particularly at the level of CYP1A2, CYP2D1/2 and CYP2D2 isoforms using the CAF/1,7-X, OZ/5-OZ and DM/DX metabolic ratios, respectively. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug–drug interactions

Pharmacological Reports ◽

10.1007/s43440-020-00089-z ◽

2020 ◽

Vol 72 (3) ◽

pp. 612-621 ◽

Cited By ~ 3

Author(s):

Jacek Wójcikowski ◽

Przemysław J. Danek ◽

Agnieszka Basińska-Ziobroń ◽

Renata Pukło ◽

Władysława A. Daniel

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Atypical Antipsychotic ◽

Antipsychotic Drug ◽

The Novel ◽

Cytochrome P450 Enzymes ◽

Atypical Antipsychotic Drug ◽

Human Cytochrome ◽

In Vitro Inhibition

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Characterization of the In Vitro Inhibitory Potential of the Oligonucleotide Imetelstat on Human Cytochrome P450 Enzymes with Predictions of In Vivo Drug-Drug Interactions

Drug Metabolism and Disposition ◽

10.1124/dmd.118.084103 ◽

2018 ◽

Vol 47 (1) ◽

pp. 9-14 ◽

Cited By ~ 3

Author(s):

Faraz Kazmi ◽

Carlo Sensenhauser ◽

Tony Greway

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Cytochrome P450 Enzymes ◽

Human Cytochrome ◽

Inhibitory Potential

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Restarting antidepressant and antipsychotic medication after intentional overdoses: need for evidence-based guidance

Therapeutic Advances in Psychopharmacology ◽

10.1177/2045125319836889 ◽

2019 ◽

Vol 9 ◽

pp. 204512531983688

Author(s):

Emma Tay ◽

Andreas Sotiriou ◽

Garry G. Graham ◽

Kay Wilhelm ◽

Leone Snowden ◽

...

Keyword(s):

Cytochrome P450 ◽

Adverse Effects ◽

Antipsychotic Drugs ◽

Plasma Concentrations ◽

Pharmacokinetic Data ◽

Psychoactive Drugs ◽

Cytochrome P450 Enzymes ◽

Psychoactive Medication ◽

Drug Overdoses ◽

P450 Inhibitors

Intentional drug overdoses with antidepressant and antipsychotic medications are an increasingly common problem. Currently, there is little guidance with regard to reintroduction of these medications after intentional overdoses. We have used published toxicological and pharmacokinetic data to obtain factors which control the recovery from overdoses. From such data, we have proposed guidance regarding their reintroduction, provided there are no adverse effects or contraindications. Tentatively, we suggest that when adverse effects from the overdose are lost, treatment could recommence after a further mean half-life of elimination. Most antidepressant and antipsychotic drugs are metabolized by cytochrome P450 enzymes and, where cytochrome P450 inhibitors are co-ingested, serial plasma concentrations should optimally be obtained in order to assess a suitable time for reintroduction of the psychoactive drugs. We hope the proposals presented will stimulate research and discussion that lead to better guidance for clinicians concerning reintroduction of psychoactive medication after intentional overdose.

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Assessment of inhibitory effects on major human cytochrome P450 enzymes by spasmolytics used in the treatment of overactive bladder syndrome

Therapeutic Advances in Urology ◽

10.1177/1756287217708951 ◽

2017 ◽

Vol 9 (7) ◽

pp. 163-177

Author(s):

Dominik Dahlinger ◽

Sevinc Aslan ◽

Markus Pietsch ◽

Sebastian Frechen ◽

Uwe Fuhr

Keyword(s):

Cytochrome P450 ◽

Liver Microsomes ◽

Fold Increase ◽

Pharmacokinetic Data ◽

Cytochrome P450 Enzymes ◽

Trospium Chloride ◽

Screening Experiments ◽

Human Cytochrome

Background: The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride on the seven major human cytochrome P450 enzymes (CYP) by using a standardized and validated seven-in-one cytochrome P450 cocktail inhibition assay. Methods: An in vitro cocktail of seven highly selective probe substrates was incubated with human liver microsomes and varying concentrations of the seven test compounds. The major metabolites of the probe substrates were simultaneously analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Enzyme kinetics were estimated by determining IC50 and Ki values via nonlinear regression. Obtained Ki values were used for predictions of potential clinical impact of the inhibition using a static mechanistic prediction model. Results: In this study, 49 IC50 experiments were conducted. In six cases, IC50 values lower than the calculated threshold for drug–drug interactions (DDIs) in the gut wall were observed. In these cases, no increase in inhibition was determined after a 30 min preincubation. Considering a typical dosing regimen and applying the obtained Ki values of 0.72 µM (darifenacin, 15 mg daily) and 7.2 µM [propiverine, 30 mg daily, immediate release (IR)] for the inhibition of CYP2D6 yielded a predicted 1.9-fold and 1.4-fold increase in the area under the curve (AUC) of debrisoquine (CYP2D6 substrate), respectively. Due to the inhibition of the particular intestinal CYP3A4, the obtained Ki values of 14 µM of propiverine (30 mg daily, IR) resulted in a predicted doubling of the AUC for midazolam (CYP3A4 substrate). Conclusions: In vitro/ in vivo extrapolation based on pharmacokinetic data and the conducted screening experiments yielded similar effects of darifenacin on CYP2D6 and propiverine on CYP3A4 as obtained in separately conducted in vivo DDI studies. As a novel finding, propiverine was identified to potentially inhibit CYP2D6 at clinically occurring concentrations.

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