scholarly journals Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marcus J. P. Geist ◽  
Victoria C. Ziesenitz ◽  
Hubert J. Bardenheuer ◽  
Juergen Burhenne ◽  
Gisela Skopp ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Real Life ◽  
Metabolic Clearance ◽  
Cyp3a Activity ◽  
Cytochrome P450 3A ◽  
Transdermal Fentanyl ◽  
Large Variability ◽  
Control Pain

Abstract Transdermal fentanyl is widely used to control pain in cancer patients. The high pharmacokinetic variability of fentanyl is assumed to be due to cytochrome P450 3A-mediated (CYP3A) N-dealkylation to norfentanyl in humans. However, recently published clinical studies question the importance of the described metabolic pathway. In this small study in palliative cancer patients under real-life clinical conditions, the influence of CYP3A on fentanyl variability was investigated. In addition to the determination of midazolam plasma concentration to reveal CYP3A activity, plasma concentrations of fentanyl and its metabolite, norfentanyl, were measured in identical blood samples of 20 patients who participated in an ongoing trial and had been on transdermal fentanyl. Fentanyl, norfentanyl, midazolam, and 1′-OH-midazolam were quantified by liquid chromatography/tandem mass spectrometry. Plasma concentrations of fentanyl and norfentanyl exhibited a large variability. Mean estimated total clearance of fentanyl and mean metabolic clearance of midazolam (as a marker of CYP3A activity) were 75.5 and 36.3 L/h. Both clearances showed a weak correlation and hence a minimal influence of CYP3A on fentanyl elimination.

Alteration of drug-metabolizing enzyme activity in palliative care patients: Microdosed assessment of cytochrome P450 3A

2019 ◽  
Vol 33 (7) ◽  
pp. 850-855
Author(s):  
Marcus Geist ◽  
Hubert Bardenheuer ◽  
Juergen Burhenne ◽  
Gerd Mikus
Keyword(s):  
Palliative Care ◽  
Cytochrome P450 ◽  
Drug Interactions ◽  
Real Life ◽  
Palliative Care Unit ◽  
Metabolic Clearance ◽  
Cytochrome P450 3A ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Clinical Conditions

Background: Cytochrome P450 3A is the most relevant drug-metabolizing enzyme in humans as it is involved in the elimination of 50% of marketed drugs. Nothing is known about the activity of cytochrome P450 3A in palliative care patients who have complicated symptoms often associated with a terminal illness. Aim: In order to improve drug dosing in end-of-life care and to avoid drug interactions, cytochrome P450 3A activity was determined in patients of a palliative care unit under real-life clinical conditions. Design: As midazolam is an established marker substance for cytochrome P450 3A activity, this single-arm prospective trial was designed to obtain a 4-h pharmacokinetic profile of midazolam after oral administration of a 10-µg dose from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1′-hydroxy-midazolam were quantified by mass spectrometry techniques. Cytochrome P450 3A activity was calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients were considered, as well as recent blood test results and patients’ diagnoses. The trial was registered at German Clinical Trials Register ( www.drks.de ): DRKS00011753. Setting/participants: The trial was carried out at a university palliative care unit under real-life clinical conditions. Every patient admitted to the ward was screened for possible participation, independent of the individual performance status. Results: Partial metabolic clearance of midazolam in palliative care patients was 31.7 ± 32.1 L/h. This was a highly significant 40% reduction ( p < 0.0001) in comparison with the cytochrome P450 3A activity of healthy subjects. Conclusion: Dosing of cytochrome P450 3A substrate drugs (e.g. macrolide antibiotics, benzodiazepines, calcium channel blockers) needs to be adjusted in palliative care patients; otherwise, escalation of debilitating symptoms due to drug interactions might occur.

Does Crizotinib Auto-Inhibit CYP3A in vivo?

Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 715-718
Author(s):  
Abigail R. Bland ◽  
Nensi Shrestha ◽  
Rhonda J. Rosengren ◽  
John C. Ashton
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Western Blot ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitor ◽  
Cyp3a Activity ◽  
Cytochrome P450 3A ◽  
Anaplastic Lymphoma

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin <i>N</i>-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo.

scholarly journals Rifampin Greatly Reduces the Plasma Concentrations of Intravenous and Oral Oxycodone

2009 ◽  
Vol 110 (6) ◽  
pp. 1371-1378 ◽  
Author(s):  
Tuija H. Nieminen ◽  
Nora M. Hagelberg ◽  
Teijo I. Saari ◽  
Antti Pertovaara ◽  
Mikko Neuvonen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Cytochrome P450 3A ◽  
Time Curve ◽  
Cold Pain ◽  
Visual Analog Scales ◽  
Concentration Time ◽  
Heat Pain Threshold ◽  
Oxycodone Hydrochloride

Background Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. Methods The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. Results Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P &lt; 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P &lt; 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P &lt; 0.001). Pharmacologic effects of oral oxycodone were attenuated. Conclusions Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

scholarly journals Inhibitory Effects of Citrus Fruits on Cytochrome P450 3A (CYP3A) Activity in Humans

2003 ◽  
Vol 26 (9) ◽  
pp. 1371-1373 ◽  
Author(s):  
Ken-ichi Fujita ◽  
Muneaki Hidaka ◽  
Norito Takamura ◽  
Keishi Yamasaki ◽  
Tomomi Iwakiri ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cyp3a Activity ◽  
Citrus Fruits ◽  
Cytochrome P450 3A ◽  
Inhibitory Effects

The Effects of Modifying In Vivo Cytochrome P450 3A (CYP3A) Activity on Etoricoxib Pharmacokinetics and of Etoricoxib Administration on CYP3A Activity

2004 ◽  
Vol 44 (10) ◽  
pp. 1125-1131 ◽  
Author(s):  
Nancy G. B. Agrawal ◽  
Catherine Z. Matthews ◽  
Ralph S. Mazenko ◽  
Eric J. Woolf ◽  
Arturo G. Porras ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cyp3a Activity ◽  
Cytochrome P450 3A

scholarly journals CYP3A Activity in End-of-Life Cancer Patients Measured by 4β-Hydroxycholesterol/cholesterol Ratio, in Men and Women

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4689
Author(s):  
Helena Bergström ◽  
Maria Helde Frankling ◽  
Caritha Klasson ◽  
Anita Lövgren Sandblom ◽  
Ulf Diczfalusy ◽  
...  
Keyword(s):  
End Of Life ◽  
Cancer Patients ◽  
Cyp3a Activity ◽  
Cytochrome P450 3A ◽  
Serum Samples ◽  
Men And Women ◽  
Cholesterol Ratio ◽  
Male Patients ◽  
Single Time Point ◽  
Time Point

More than 50% of all drugs are metabolized by the cytochrome P450 3A enzyme (CYP3A). The aim of this study was to investigate if the CYP3A activity, measured by the endogenous marker 4β-hydroxycholesterol/cholesterol ratio (4β-OHC/C), is changed during the last weeks and days of life in men and women. To this end, serum samples from 137 deceased patients (median age 70 years) collected at a single time point 1–60 days before death, were analyzed and compared to 280 young (median 27 years), and 30 elderly (median age 70 years) non-cancer controls. There were no significant differences in the 4β-OHC/C ratio between men and women in end-of-life patients (p < 0.25). The median 4β-OHC/C was significantly higher in end-of-life male patients compared to both young (p < 0.0001) and elderly (p < 0.05) male controls. In a similar manner, 4β-OHC/C in end-of-life female patients was significantly higher compared to young and elderly female controls, p < 0.0001 and p < 0.001, respectively. There was no significant correlation between 4β-OHC/C and survival time. The results from this study suggest maintained CYP3A activity to the very last days of life and even a capacity of induction of the enzyme in end-of-life cancer patients.

scholarly journals Erlotinib treatment induces cytochrome P450 3A activity in non‐small cell lung cancer patients

2019 ◽  
Vol 85 (8) ◽  
pp. 1704-1709 ◽  
Author(s):  
Anna Svedberg ◽  
Svante Vikingsson ◽  
Anders Vikström ◽  
Niels Hornstra ◽  
Magnus Kentson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Cytochrome P450 3A ◽  
Small Cell Lung ◽  
Lung Cancer Patients
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