Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.

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Iatrogenic Cushing syndrome and multifocal osteonecrosis caused by the interaction between inhaled fluticasone and ritonavir

BMJ Case Reports ◽

10.1136/bcr-2019-233712 ◽

2020 ◽

Vol 13 (5) ◽

pp. e233712 ◽

Cited By ~ 2

Author(s):

Joana Figueiredo ◽

Margarida Serrado ◽

Nikita Khmelinskii ◽

Sónia do Vale

Keyword(s):

Cytochrome P450 ◽

Clinical Case ◽

Inhaled Corticosteroids ◽

Cushing Syndrome ◽

Plasma Concentrations ◽

Hepatic Metabolism ◽

Cytochrome P450 3A4 ◽

Systemic Accumulation ◽

Pituitary Adrenal Axis ◽

Relevant Interaction

Inhaled corticosteroids are generally considered safe and do not usually lead to systemic adverse events since their plasma concentrations are low due to hepatic metabolism by the cytochrome P450 3A4. However, when associated with inhibitors of this cytochrome, such as ritonavir, they may lead to iatrogenic Cushing syndrome by the systemic accumulation of corticosteroids and consequent suppression of the hypothalamic-pituitary-adrenal axis. We present a case of iatrogenic Cushing syndrome complicated by multifocal osteonecrosis in a patient with HIV infection on antiretroviral therapy with protease inhibitors boosted with ritonavir, after the association of inhaled fluticasone. This clinical case highlights a relevant interaction between corticosteroids and inhibitors of the cytochrome P450 and the severe consequences that may occur.

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Fatty Liver and Impaired Hepatic Metabolism Alters the Congener-Specific Distribution of Polychlorinated Biphenyls (PCBs) in Mice with a Liver-Specific Deletion of Cytochrome P450 Reductase

10.26434/chemrxiv.12026904.v1 ◽

2020 ◽

Author(s):

Xueshu Li ◽

Chun-Yun Zhang ◽

Hans-Joachim Lehmler

Keyword(s):

Cytochrome P450 ◽

Polychlorinated Biphenyls ◽

Fatty Liver ◽

Partition Coefficients ◽

Hepatic Metabolism ◽

Gas Chromatography Mass Spectrometry ◽

Cytochrome P450 Reductase ◽

P450 Reductase ◽

Specific Distribution ◽

Specific Deletion

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that are linked to adverse health outcomes. PCB tissue levels are determinants of PCB toxicity; however, it is unclear how factors, such as an altered metabolism and/or a fatty liver, affect PCB distribution in vivo. We determined the congener-specific disposition of PCBs in mice with a liver specific deletion of cytochrome P450 reductase (KO), a model of fatty liver with impaired hepatic metabolism, and wildtype (WT) mice. Male and female KO and WT mice were exposed orally to Aroclor 1254, a technical PCB mixture. PCBs were quantified in adipose, blood, brain and liver tissues by gas chromatography-mass spectrometry. PCB profiles and levels in tissues were genotype and sex dependent. PCB levels were higher in the liver from KO compared to WT mice. PCB profiles showed clear differences between tissues from the same exposure group. While experimental tissue : blood partition coefficients in KO and WT mice did not follow the trends predicted using a composition-based model, the agreement between experimental and calculated partition coefficients was still reasonable. Thus, a fatty liver and/or an impaired hepatic metabolism alter the distribution of PCBs in mice and the magnitude of the partitioning of PCBs from blood into tissues can be approximated using composition-based models.<br>

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