Dose–response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles

Strauch, Katja; Lutz, Ursula; Bittner, Nataly; Lutz, Werner

doi:10.1016/j.fct.2009.05.004

Cited by 21 publications

(12 citation statements)

References 43 publications

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“…According to the last toxicological evaluation [ 38 , 39 , 40 , 41 , 42 ], the quality control of these compounds in food represents an emerging subject and the development of an analytical method suitable for this purpose is a challenge. The information derived by the characterization of several types of beverages provides a starting point to discuss the dietary intake of FCs and below which value it can be considered safe.…”

Section: Discussionmentioning

confidence: 99%

“…No limits are imposed on the content of FCs in food, but as mentioned above, they can seriously affect drug metabolism due to the inhibition of the isoform CYP3A4 of cytochrome P450 [ 38 ] and the inhibition of efflux transporters [ 39 ]. The increase in bioavailability of many drugs can lead to cardiac disorders and respiratory depression [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Dietary Intake of Coumarins and Furocoumarins through Citrus Beverages: A Detailed Estimation by a HPLC-MS/MS Method Combined with the Linear Retention Index System

Arigò

Rigano

Russo

et al. 2021

Foods

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Official regulations concerning the maximum number of substances in food are introduced as a consequence of possible adverse effects, after oral administration. In this regard, analytical methods are necessary in order to determine specific targets. Among oxygen heterocyclic compounds (OHCs, that are furocoumarins, coumarins and polymethoxyflavones), only coumarin is subject to restriction by the Regulation (EC) No 1334/2008 of the European Parliament. Furocoumarins are known for their phototoxicity and other side effects due to their dietary intake; however, an official limit about the maximum content of these compounds in food is still missing. The lack of information about the real amount of these compounds in food is responsible for the conflicting opinions about the introduction of an official limit. The HPLC-MS/MS method here proposed, in combination with the linear retention index system, represents an innovative analytical strategy for the characterization of OHCs in citrus beverages. Several types of drinks were analysed in order to quantify 35 OHCs in total. This method is suitable for the quality control of OHCs in food and the obtained results may be considered as informative data useful for the regulatory authorities in the emission of new opinions and for a potential new regulation in this field.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dietary Intake of Coumarins and Furocoumarins through Citrus Beverages: A Detailed Estimation by a HPLC-MS/MS Method Combined with the Linear Retention Index System

Arigò

Rigano

Russo

et al. 2021

Foods

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show abstract

“…Despite the known health benefits of grapefruit juice, its consumption in combination with drugs requires great caution and patient education by health care professionals [10]. A single glass of grapefruit juice or one whole grapefruit has sufficient potency to cause a clinically significant pharmacokinetic interaction with a dose-dependent magnitude and significance [11].…”

Section: Introductionmentioning

confidence: 99%

Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects

Abdlekawy

Donia

Elbarbry

2016

Eur J Drug Metab Pharmacokinet

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“…DXM can be administered orally and intravenously, has low bioavailability (≈50%) and a rapid first-pass effect in the intestine and liver. Typically only about half of the dose is recovered in urine over at least 12 hours after administration, primarily as glucuronides (Schadel et al, 1995; Capon et al, 1996; Tennezé et al, 1999; Strauch et al, 2009). In the systemic circulation, ≈55-65% of DXM is non-specifically bound to plasma proteins (Lutz and Isoherranen, 2012; Taylor et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan

Grzegorzewski

Brandhorst

König

2022

Preprint

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The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of dextromethorphan (DXM) and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model of CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as measured by AS, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping with dextromethorphan using the urinary cumulative metabolic ratio DXM/(DXO+DXO-Glu) (UCMR). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied as a tool for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.

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Dose–response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles

Cited by 21 publications

References 43 publications

Dietary Intake of Coumarins and Furocoumarins through Citrus Beverages: A Detailed Estimation by a HPLC-MS/MS Method Combined with the Linear Retention Index System

Dietary Intake of Coumarins and Furocoumarins through Citrus Beverages: A Detailed Estimation by a HPLC-MS/MS Method Combined with the Linear Retention Index System

Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects

Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan

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