Expert Opinion on Drug Metabolism & Toxicology

INTRODUCTION: Methotrexate (MTX) is an anti-folate and immunosuppressive drug prescribed for various malignancies and immune diseases. However, delayed elimination of MTX associated with concomitant use of some medications can lead to severe and life-threatening adverse effects. AREAS COVERED: This paper investigated drug-MTX interactions that lead to elevated MTX levels and related adverse effects due to the role of transporters. Methotrexate toxicity occurs at both low and high doses administrations...

INTRODUCTION: Busulfan is an alkylating agent widely used in the conditioning of hematopoietic stem cell transplantation possessing a complex metabolism and a large interindividual and intra-individual variability, especially in children. Combined with the strong rationale of busulfan PK/PD relationships, factors altering its clearance (e.g., weight, age, and GST-A genetic polymorphism mainly) can also affect clinical outcomes. AREAS COVERED: This review aims to provide an overview of the current knowledge on busulfan pharmacokinetics, its pharmacokinetics variabilities in pediatric populations, drug-drug interactions (DDI), and their consequences regarding dose individualization...

No abstract text is available yet for this article.

INTRODUCTION: Antipsychotics (APs), during treatment or overdose, may be associated with respiratory aspiration. AREAS COVERED: A PubMed search on September 30, 2022, provided 3 cases of respiratory aspiration during clozapine therapy and 1 case during an AP overdose. VigiBase records of respiratory aspiration associated with APs from inception until September 5, 2021, were reviewed. VigiBase, the World Health Organization's global pharmacovigilance database, uses a statistical signal for associations called the information component (IC)...

No abstract text is available yet for this article.

BACKGROUND: Apixaban is a superior direct oral anticoagulant exihibiting interindividual variability in concentration and response in the real world. The present study aimed to identify genetic biomarkers associated with pharmacokinetics (PK) and pharmacodynamics (PD) of apixaban in healthy Chinese subjects. METHODS: This multicenter study included 181 healthy Chinese adults taking a single dose of 2.5 mg or 5 mg apixaban and assessed their PK and PD parameters...

INTRODUCTION: In the United States, obesity affects approximately ⅖ adults and ⅕ children, leading to increased risk for comorbidities, like gastroesophageal reflux disease (GERD), treated increasingly with proton pump inhibitors (PPIs). Currently, there are no clinical guidelines to inform PPI dose selection for obesity, with sparse data regarding whether dose augmentation is necessary. AREAS COVERED: We provide a review of available literature regarding the pharmacokinetics (PK), pharmacodynamics (PD), and/or metabolism of PPIs in children and adults with obesity, as a step toward informing PPI dose selection...

INTRODUCTION: Determining antibiotic exposure in the lung and the threshold(s) needed for effective antibacterial killing is paramount during development of new antibiotics for the treatment of nosocomial pneumonia, as these exposures directly affect clinical outcomes and resistance development. The use of pharmacokinetic and pharmacodynamic modeling is recommended by regulatory agencies to evaluate antibiotic pulmonary exposure and optimize dosage regimen selection. This process has been implemented in newer antibiotic development...

INTRODUCTION: Various pharmacogenomic (PGx) variants differ widely in different ethnicities. and clinical outcomes associated with these variants may also be substantially varied. Literature was searched in different databases, i.e. PubMed, ScienceDirect, Web of Science, and PharmGKB, from inception to 30 June 2022 for this review. AREAS COVERED: Certain PGx variants were distinctly varied in Asian populations compared to the other human populations, e.g. CYP2C19 * 2,*3,*17; CYP2C9*2,*3; CYP2D6*4,*5,*10,*41; UGT1A1*6,*28; HLA-B*15:02, HLA-B*15:21, HLA-B*58:01 , and HLA-A*31:01 ...

BACKGROUND: 4-hydroxy- N,N ,methylpropyltryptamine (4-OH-MPT) is a psychedelic tryptamine whose use is regulated in several countries. Due to unspecific effects, consumption can be ascertained only through toxicological analyses. However, the trace amounts of tryptamines usually are challenging to detect in biological samples. 4-OH-MPT metabolism was characterized to identify optimal metabolite markers of intake in clinical/forensic toxicology. RESEARCH DESIGN AND METHODS: 4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate in vivo conditions; samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and data were processed with Compound Discoverer from Thermo Scientific...

INTRODUCTION: Clopidogrel is the only antiplatelet agent whose activity is significantly affected by CYP2C19 polymorphism. AREAS COVERED: This review has summarized the available evidence on the clinically significant association between CYP2C19 polymorphism and clopidogrel-based therapy; reviewed the current recommendations for clinical use of CYP2C19 genotype test results in patients on clopidogrel treatment; and discussed possible pitfalls of routine application, and future perspectives of antiplatelets pharmacogenetics...

INTRODUCTION: CYP2D6 contributes to the metabolism of approximately 20-25% of drugs. However, CYP2D6 is highly polymorphic and different alleles can lead to impacts ranging from null to increase in activity. Moreover, there are commonly used drugs that potently inhibit the CYP2D6, thus causing 'phenoconversion' which can convert the genotypic normal metabolizer into phenotypic poor metabolizer. Despite growing literature on the clinical implications of non-normal CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing is rare...

INTRODUCTION: The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population. AREAS COVERED: This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab...

INTRODUCTION: Interstitial lung disease (ILD) or pneumonitis remains an important adverse event identified with treatment with antibody-drug conjugates (ADCs). Drug-induced ILD (DILD) accounts for 3%-5% of common ILD cases and is a significant problem in clinical practice. Hence, with the anticipation of the widespread use of ADCs, it will be important for guidelines and recommendations to be established to direct and standardize the management of DILD by a multidisciplinary team (MDT)...

INTRODUCTION: Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown. AREAS COVERED: Relevant literature was searched for in the MEDLINE (from 1964 until August 31st , 2022), SCOPUS (from 2004 until August 31st , 2022) and GOOGLE SCHOLAR (from 2004 until August 31st , 2022) databases, without restriction in terms of publication date...

INTRODUCTION: : The kidney is vulnerable to various injuries based on its function in the elimination of many xenobiotics, endogenous substances and metabolites. Since transporters are critical for the renal elimination of those substances, it is urgent to understand the emerging role of transporters in nephrotoxicity. AREAS COVERED: : This review summarizes the contribution of major renal transporters to nephrotoxicity induced by some drugs or toxins; addresses the role of transporter-mediated endogenous metabolic disturbances in nephrotoxicity; and discusses the advantages and disadvantages of in vitro models based on transporter expression and function...

INTRODUCTION: Patients with severe mental illness (SMI) have a high risk for diabetes, dyslipidemia, and other components of metabolic syndrome. Patients with these metabolic comorbidities and cardiac risk factors should receive not only antipsychotics but also medications aiming to reduce cardiovascular risk. Therefore, many patients may be exposed to clinically relevant drug-drug interactions. AREAS COVERED: This narrative review summarizes data regarding the known or potential drug-drug interactions between antipsychotics and medications treating metabolic syndrome components, except for hypertension, which has been summarized elsewhere [1]...

INTRODUCTION: Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed. AREAS COVERED: VigiBase provided a significant myocarditis IC = 4...

INTRODUCTION: Fingolimod was the first oral disease-modifying treatment approved for relapsing-remitting multiple sclerosis (MS) that serves as a sphingosine-1-phosphate receptor (S1PR) agonist. The efficacy is primarily mediated by S1PR subtype 1 activation, leading to agonist-induced down-modulation of receptor expression and further functional antagonism, blocking the egression of auto-aggressive lymphocytes from the lymph nodes in the peripheral compartment. The role of S1P signaling in the regulation of other pathways in human organisms through different S1PR subtypes has received much attention due to its immune-modulatory function and its significance for the regeneration of the central nervous system (CNS)...

INTRODUCTION: The proton-coupled folate transporter (PCFT; SLC46A1) was discovered in 2006 as the principal mechanism by which folates are absorbed in the intestine and the causal basis for hereditary folate malabsorption (HFM). In 2011, it was found that PCFT is highly expressed in many tumors. This stimulated interest in using PCFT for cytotoxic drug targeting, taking advantage of the substantial levels of PCFT transport and acidic pH conditions commonly associated with tumors. AREAS COVERED: We summarize the literature from 2006-2022 that explores the role of PCFT in the intestinal absorption of dietary folates and its role in HFM, and as a transporter of folates and antifolates such as pemetrexed (Alimta) in relation to cancer...