Expert Opinion on Drug Metabolism & Toxicology最新文献

Introduction: The effects of antipsychotic drugs are dose-dependent, which is particularly true for their efficacy, each antipsychotic having a specific dose-response curve. This may justify individualizing doses for these agents.

Areas covered: We review the pharmacokinetic profiles of seven oral antipsychotics: haloperidol, risperidone, olanzapine, clozapine, quetiapine, ziprasidone, and aripiprazole. Their main indications are psychotic and affective disorders. They are prescribed in a very large population which may have comorbidities. Hence, we analyze the impact of the latter on the pharmacokinetic profiles of these antipsychotics, focusing on renal and hepatic impairment. Reviews and clinical trials were discussed based on a systematic literature search (PubMed) ranging from 1995 to 2022.

Expert opinion: Factors liable to impact antipsychotic dosage are numerous and their subsequent effects often hard to predict, due to multilevel interactions and compensatory phenomena. In clinical practice, physicians must be aware of these potential effects, but base their decisions on monitoring antipsychotic plasma levels.

Introduction: Idiosyncratic drug-induced liver injury (IDILI) causes morbidity and mortality in patients and leads to curtailed use of efficacious pharmaceuticals. Unlike intrinsically toxic reactions, which depend on dose, IDILI occurs in a minority of patients at therapeutic doses. Much remains unknown about causal links among drug exposure, a mode of action, and liver injury. Consequently, numerous hypotheses about IDILI pathogenesis have arisen.

Areas covered: Pharmacokinetic and toxicodynamic characteristics underlying current hypotheses of IDILI etiology are discussed and illustrated graphically.

Expert opinion: Hypotheses to explain IDILI etiology all involve alterations in pharmacokinetics, which lead to plasma drug concentrations that rise above a threshold for toxicity, or in toxicodynamics, which result in a lowering of the toxicity threshold. Altered pharmacokinetics arise, for example, from changes in drug metabolism or from transporter polymorphisms. A lowered toxicity threshold can arise from drug-induced mitochondrial injury, accumulation of toxic endogenous factors or harmful immune responses. Newly developed, interactive freeware (DemoTox-PK; https://bit.ly/DemoTox-PK) allows the user to visualize how such alterations might lead to a toxic reaction. The illustrations presented provide a framework for conceptualizing idiosyncratic reactions and could serve as a stimulus for future discussion, education, and research into modes of action of IDILI.

Introduction: Nucleoside analogs are an important class of antiviral agents. Due to the high hydrophilicity and limited membrane permeability of antiviral nucleoside/nucleotide analogs (AVNAs), transporters play critical roles in AVNA pharmacokinetics. Understanding the properties of these transporters is important to accelerate translational research for AVNAs.

Areas covered: The roles of key transporters in the pharmacokinetics of 25 approved AVNAs were reviewed. Clinically relevant information that can be explained by the modulation of transporter functions is also highlighted.

Expert opinion: Although the roles of transporters in the intestinal absorption and renal excretion of AVNAs have been well identified, more research is warranted to understand their roles in the distribution of AVNAs, especially to immune privileged compartments where treatment of viral infection is challenging. P-gp, MRP4, BCRP, and nucleoside transporters have shown extensive impacts in the disposition of AVNAs. It is highly recommended that the role of transporters should be investigated during the development of novel AVNAs. Clinically, co-administered inhibitors and genetic polymorphism of transporters are the two most frequently reported factors altering AVNA pharmacokinetics. Physiopathology conditions also regulate transporter activities, while their effects on pharmacokinetics need further exploration. Pharmacokinetic models could be useful for elucidating these complicated factors in clinical settings.

Introduction: Members of the solute carrier family of organic anion transporting polypeptides are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. In particular, the polymorphic transporters OATP1B1 and OATP1B3 are highly expressed in the liver and have been identified as critical regulators of hepatic elimination. As these transporters are also expressed in cancer cells, the function alteration of these proteins have important consequences for an individual's susceptibility to certain drug-induced side effects, drug-drug interactions, and treatment efficacy.

Areas covered: In this mini-review, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of genetic variants in OATP1B1 and OATP1B3 to the transport of anticancer drugs, the role of these carriers in regulation of their disposition and toxicity profiles, and recent advances in attempts to integrate information on transport function in patients to derive individualized treatment strategies.

Expert opinion: Based on currently available data, it appears imperative that different aspects of disease, physiology, and drugs of relevance should be evaluated along with an individual's genetic signature, and that tools such as biomarker levels can be implemented to achieve the most reliable prediction of clinically relevant pharmacodynamic endpoints.

Introduction: Uterine fibroids are the most common benign gynecological tumors affecting women of reproductive ages. Although surgery is the definitive treatment choice, several medical approaches have been investigated to control their symptoms. The main issue of currently employed drugs for uterine fibroids is the long-term safety and tolerability profile. Today, new emerging options represent hopeful alternatives that could potentially overcome these limitations.

Areas covered: This manuscript aims to give an updated overview of the pharmacodynamic and pharmacokinetic properties of current and new investigational medical drugs for the treatment of symptomatic uterine fibroids. The bibliographic research was conducted by searching alone or combined keywords on the following electronic databases: Medline, PubMed, Embase, Science Citation Index via Web of Science.

Expert opinion: The most recent therapeutic strategies for uterine fibroids are represented by gonadotropin-releasing hormone antagonists (GnRH-ants; elagolix and relugolix) and selective progesterone receptor modulators (SPRM; ulipristal acetate). After early promising results, studies on innovative drugs, such as linzagolix (GnRH-ant) and vilaprisan (SPRM) are demanding. In the near future, a deeper knowledge of biological mechanisms at the basis of the genesis and growth of uterine fibroids could pave the way for the development of innovative targeted therapies.

Introduction: Cytochrome P450s (CYPs) are a superfamily of monooxygenases with diverse biological roles. CYP2J2 is an isozyme highly expressed in the heart where it metabolizes endogenous substrates such as N-3/N-6 polyunsaturated fatty acids (PUFA) to produce lipid mediators involved in homeostasis and cardioprotective responses. Expanding our knowledge of the role CYP2J2 has within the heart is important for understanding its impact on cardiac health and disease.

Areas covered: The objective of this review was to assess the state of knowledge regarding cardiac CYP2J2. A literature search was conducted using PubMed-MEDLINE (from 2022 and earlier) to evaluate relevant studies regarding CYP2J2-mediated cardioprotection, small molecule modulators, effects of CYP2J2 substrates toward biologically relevant effects and implications of CYP2J2 polymorphisms and sexual dimorphism in the heart.

Expert opinion: Cardiac CYP2J2-mediated metabolism of endogenous and exogenous substrates have been shown to impact cardiac function. Identifying individual factors, like sex and age, that affect CYP2J2 require further elucidation to better understand CYP2J2's clinical relevance. Resolving the biological targets and activities of CYP2J2-derived PUFA metabolites will be necessary to safely target CYP2J2 and design novel analogues. Targeting CYP2J2 for therapeutic aims offers a potential novel approach to regulating cardiac homeostasis, drug metabolism and cardioprotection.

Background: Tacrolimus is a immunosuppressant drug in transplantation with a narrow therapeutic range and high pharmacokinetic variability. Clinical studies have revealed that POR*28 contributes enhanced tacrolimus clearance in CYP3A5 expressers. However, it remains unknown that how exactly the POR polymorphism could influence the metabolism of tacrolimus via CYP3A5 in vitro.

Research design & methods: A503V is an amino acid sequence variant encoded by POR*28. Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant (K_m) and maximum velocity (V_max) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as V_max/K_m.

Results: Both WT and A503V POR down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein levels.

Conclusion: A503V can affect CYP3A5-catalyzed tacrolimus metabolism in vitro, which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.

Introduction: Heart failure (HF) is becoming a huge public health burden. New diabetes drugs for type 2 diabetes (T2D), sodium-glucose cotransporter type 2 inhibitors (SGLT2is), reduce the rate of hospitalization for HF in placebo-controlled trials.

Areas covered: Pharmacokinetics of dapagliflozin and empagliflozin (in presence of renal impairment and hepatic dysfunction, two comorbidities frequently associated with HF) and pharmacodynamic studies in patients with HF. Main HF outcomes in T2D patients with cardiovascular risk and in patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction, with or without T2D, from DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved original findings and post hoc analyses.

Expert opinion: No clinically relevant changes are expected concerning SGLT2i pharmacokinetics in patients with HF while pharmacodynamic studies reported improvements in myocardium/vascular parameters, biomarkers, and functional status. All SGLT2is showed a remarkable reduction in hospitalization for HF in patients with T2D and high cardiovascular risk. Furthermore, both dapagliflozin and empagliflozin improved the prognosis of patients with HFrEF, independently of the presence of T2D. Similar results were reported with empagliflozin in patients with HFpEF, to be confirmed with dapagliflozin in an ongoing trial (DELIVER). Thus, SGLT2is offer a new opportunity for the prevention and management of HF in patients with or without T2D.

Introduction: Although not a potentially life-threatening poisoning, benzodiazepine (BZD) intoxication may be life-threatening in special situations/populations or those with background diseases.

Areas covered: The aim of this review is to evaluate all possible treatment options available in the literature for the management of benzodiazepine poisoning with special attention to antidote administration. We conducted a literature search using PubMed, Google Scholar, EMBASE, and Cochrane central register from 1 January 1980 to 10 November 2021 using keywords 'benzodiazepine,' 'poisoning,' 'toxicity,' 'intoxication,' and 'treatment.'

Expert opinion: Careful patient selection, ideally by a clinical toxicologist, may decrease the complications of flumazenil and add to its efficacy. The cost-to-benefit ratio should be considered in every single patient who is a candidate for flumazenil administration. In case a decision has been made to administer flumazenil, careful consideration of the possible contraindications is essential. We recommend slow administration of low doses of flumazenil (0.1 mg/minute) to avoid complications or withhold the administration with development of first signs of adverse effects. The main treatment of benzodiazepine toxicity is conservative with administration of activated charcoal, monitoring of the vital signs, prevention of aspiration and development of deep vein thrombosis due to prolonged immobilization, and respiratory support.

Introduction: Hepatic drug metabolism is important in improving drug dosing strategies in sepsis. Pharmacokinetics in the critically ill population are severely altered due to changes in absorption, distribution, excretion and metabolization. Hepatic drug metabolism might be altered due to changes in hepatic blood flow, drug metabolizing protein availability, and protein binding. The purpose of this review is to examine evidence on whether hepatic drug metabolism is significantly affected in septic patients, and to provide insights in the need for future research.

Areas covered: This review describes the effect of sepsis on hepatic drug metabolism in humans. Clinical trials, pathophysiological background information and example drug groups are further discussed. The literature search has been conducted in Embase, Medline ALL Ovid, and Cochrane CENTRAL register of trials.

Expert opinion: Limited research has been conducted on drug metabolism in the sepsis population, with some trials having researched healthy individuals using endotoxin injections. Notwithstanding this limitation, hepatic drug metabolism seems to be decreased for certain drugs in sepsis. More research on the pharmacokinetic behavior of hepatic metabolized drugs in sepsis is warranted, using inflammatory biomarkers, hemodynamic changes, mechanical ventilation, organ support, and catecholamine infusion as possible confounders.