Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

Conney, Allan H.; Reidenberg, Marcus M.

doi:10.1124/jpet.112.193193

Cited by 11 publications

(11 citation statements)

References 38 publications

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“…This is relevant because cigarette smoking is known to induce P450 1A. 31 P450 2D6 was capable of generating M5 in vitro, as demonstrated from incubations with recombinant enzyme and human liver microsomal fractions; however, P450 2D6 is likely not a significant contributor to sunitinib reactive metabolite generation based on its low catalytic efficiency observed in kinetic assays. M3 and M5 were also formed by the extrahepatic P450s 1A1 and 2J2.…”

Section: Discussionmentioning

confidence: 99%

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Amaya

Durandis

Bourgeois

et al. 2018

Chem. Res. Toxicol.

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Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography–tandem mass spectrometry. A putative quinoneimine–GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl–GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.

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Section: Discussionmentioning

confidence: 99%

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Amaya

Durandis

Bourgeois

et al. 2018

Chem. Res. Toxicol.

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“…Smoking is one of the main factors contributing to the variability of riociguat exposure; quantitative variations in smoking habits or other environmental or dietary factors that induce CYP1A1 (e.g. consumption of cruciferous vegetables or charcoal-broiled meat [ 55 , 56 ]) may contribute to interindividual variability in the separate subpopulations of smokers and non-smokers [ 15 ]. However, there is no reason to suspect that these factors differed substantially between smokers and non-smokers in the riociguat studies, and the effect of smoking on riociguat exposure has been observed in studies controlled for diet and environment [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat

et al. 2017

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Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)–sGC–cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food and as crushed or whole tablets. Riociguat exposure shows pronounced interindividual (60%) and low intraindividual (30%) variability in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), and is therefore administered using an individual dose-adjustment scheme at treatment initiation. The half-life of riociguat is approximately 12 h in patients and approximately 7 h in healthy individuals. Riociguat and its metabolites are excreted via both renal (33–45%) and biliary routes (48–59%), and dose adjustment should be performed with particular care in patients with moderate hepatic impairment or mild to severe renal impairment (no data exist for patients with severe hepatic impairment). The pharmacodynamic effects of riociguat reflect the action of a vasodilatory agent, and the hemodynamic response to riociguat correlated with riociguat exposure in patients with PAH or CTEPH in phase III population pharmacokinetic/pharmacodynamic analyses. Riociguat has a low risk of clinically relevant drug interactions due to its clearance by multiple cytochrome P450 (CYP) enzymes and its lack of effect on major CYP isoforms and transporter proteins at therapeutic levels. Riociguat has been approved for the treatment of PAH and CTEPH that is inoperable or persistent/recurrent after surgical treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0604-7) contains supplementary material, which is available to authorized users.

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“…Alcohol and drug use, including opioids, cocaine, and methamphetamines, have a major dose–response influence on medication adherence and interactions with commonly prescribed medications [68, 112–115]. Alcohol and tobacco can influence drug clearance and activity levels directly and through effects on liver and kidney function, with important clinical impacts [116–119]. Use of controlled medications other than how they were prescribed or solely for the effect they provide (non-medical use) can result in over-sedation, overdose and death [120–122].…”

Section: Factors Contributing To Polypharmacy’s Harmsmentioning

confidence: 99%

The Next Therapeutic Challenge in HIV: Polypharmacy

et al. 2013

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With the adoption of combination antiretroviral therapy (ART), most HIV-infected individuals in care are on five or more medications and at risk of harm from polypharmacy, a risk that likely increases with number of medications, age, and physiologic frailty. Established harms of polypharmacy include decreased medication adherence and increased serious adverse drug events, including organ system injury, hospitalization, geriatric syndromes (falls, fractures, and cognitive decline) and mortality. The literature on polypharmacy among those with HIV infection is limited, and the literature on polypharmacy among non-HIV patients requires adaptation to the special issues facing those on chronic ART. First, those aging with HIV infection often initiate ART in their 3rd or 4th decade of life and are expected to remain on ART for the rest of their lives. Second, those with HIV may be at higher risk for age-associated comorbid disease, further increasing their risk of polypharmacy. Third, those with HIV may have an enhanced susceptibility to harm from polypharmacy due to decreased organ system reserve, chronic inflammation, and ongoing immune dysfunction. Finally, because ART is life-extending, nonadherence to ART is particularly concerning. After reviewing the relevant literature, we propose an adapted framework with which to address polypharmacy among those on lifelong ART and suggest areas for future work.

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Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

Cited by 11 publications

References 38 publications

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat

The Next Therapeutic Challenge in HIV: Polypharmacy

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