Drug Metabolism and Disposition : the Biological Fate of Chemicals

Camonsertib is a novel ATR kinase inhibitor in clinical development for advanced cancers targeting sensitizing mutations. This article describes the identification and biosynthesis of an N-glucuronide metabolite of camonsertib. This metabolite was first observed in human hepatocyte incubations and was subsequently isolated to determine the structure, evaluate its stability as part of bioanalytical method development and for use as a standard for estimating its concentration in Phase I samples. The N-glucuronide was scaled-up using a purified bacterial culture preparation and was subsequently isolated using preparative chromatography...

BIIB104 (formerly PF-04958242), N -((3 S ,4 S )-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an AMPAR potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O -dealkylation in all 3 species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile-14 C]BIIB104 showed incomplete recovery of administered radioactivity (~80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life...

It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of about 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system ECCS class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes (RLM) in the presence and absence of 5% plasma...

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution...

Gemcitabine (dFdC) and emtricitabine (FTC) are first-line drugs that are used for the treatment of pancreatic cancer and HIV, respectively. The above drugs must undergo sequential phosphorylation to become pharmacologically active. Interindividual variability associated with the responses of the above drugs has been reported. The molecular mechanisms underlying the observed variability are yet to be elucidated. Although this could be multifactorial, nucleotidases may be involved in the dephosphorylation of drug metabolites due to their structural similarity to endogenous nucleosides...

Accurate predictions of renal drug-drug interactions (DDIs) mediated by the human organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins (hMATEs) remain challenging. Current DDI evaluation using plasma maximal unbound inhibitor concentrations (Imax,u ) and IC50 values determined in single transporter-transfected cells frequently leads to false or overprediction especially for hMATE1. Emerging evidence suggests intracellular unbound inhibitor concentration may be more relevant for hMATE1 inhibition in vivo...

Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and academic research. The use of PBPK models is continuously expanding with the majority of work now focusing on predictions of drug-drug interactions, drug-disease interactions, and changes in drug disposition across lifespan. Recently, publications that use PBPK modeling to predict drug disposition during pregnancy and in organ impairment have increased reflecting the advances in incorporating diverse physiological changes into the models...

Humans are chronically exposed to benzalkonium chlorides (BACs) from environmental sources. The FDA has recently called for additional BAC safety data, as these compounds are cytotoxic and with great potential for biochemical interactions. Biodistribution studies revealed that BACs extensively distribute to many tissues and accumulate at high levels, especially in the kidneys, but the underlying mechanisms are unclear. In this study, we characterized the interactions of BACs of varying alkyl chain length (C8 to C14) with the human organic cation transporters (hOCT1-3) and multidrug and toxin extrusion proteins (hMATE1/2K) with the goal to identify transporters that could be involved in BAC disposition...

Human microbiomes, particularly in the gut, could have a major impact on efficacy and toxicity of the drugs. However, gut microbial metabolism is often neglected in the drug discovery and development process. Medicen, a Paris-based human health innovation cluster, has gathered more than thirty international leading experts from pharma, academia, biotech, CROs and regulatory affairs to develop proposals to facilitate integration of the microbiome in drug discovery and development. Seven subteams were implemented to cover the complementary expertise areas of 1) Pharma experience and case studies, 2) in silico microbiome-drug interaction, 3) in vitro microbial stability screening, 4) gut fermentation models, 5) animal models, 6) microbiome integration in clinical and regulatory aspects, and 7) microbiome standards...

The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is the organ massively exposed to gut microbial metabolites, and it serves as the nexus, maintaining healthy interactions between the gut microbiota and host. At the same time, the liver is the primary target of harmful gut microbial metabolites. This review provides an up-to-date list of gut microbial metabolites identified to increase or decrease host susceptibility to APAP-induced liver injury...

Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiological and pathological conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biological functions. Till now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithms tools indicated a low propensity of PXR to undergo phase separation...

Physiologically-based pharmacokinetic (PBPK) modeling is a mechanistic dynamic modeling approach that can be used to predict or retrospectively describe changes in drug exposure due to drug-drug interactions. With advancements in commercially available PBPK software, PBPK DDI modeling has become a mainstream approach from early drug discovery through to late stage drug development and is often utilized to support regulatory packages for new drug applications. This minireview will briefly describe the approaches to predicting DDI utilizing PBPK and static modeling approaches, the basic model structures and features inherent to PBPK DDI models and key examples where PBPK DDI models have been used to describe complex DDI mechanisms...

Small molecule kinase inhibitors are one of the fastest growing classes of drugs, which are approved by the US Food and Drug Administration (FDA) for cancer and non-cancer indications. As of September 2023, there were over 70 FDA-approved small molecule kinase inhibitors on the market, 42 of which were approved in the past five years (2018-2023). This minireview discusses recent advances in our understanding of the pharmacology, metabolism, and toxicity profiles of recently approved kinase inhibitors with a central focus on tyrosine kinase inhibitors (TKIs)...

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is FDA-approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged one year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate (VPA), another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health...

The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by CYP3A7 in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development...

Tree shrews are a non-primate species used in a range of biomedical studies. Recent genome analysis of tree shrews found that the sequence identities and the numbers of genes of cytochromes P450 (CYP or P450s), an important family of drug-metabolizing enzymes, are similar to those of humans. However, tree shrew P450s have not yet been sufficiently identified and analyzed. In this study, novel CYP2D8a and CYP2D8b cDNAs were isolated from tree shrew liver and were characterized, along with human CYP2D6, dog CYP2D15, and pig CYP2D25...

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The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity...

The administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism and excretion (ADME) studies for small molecule drugs, since it allows facile and accurate quantification of parent drug, metabolites and total drug related material independent of the compound structure. The choice of the position of the radiolabel, typically 14 C or 3 H, is critical to obtain relevant information. Sometimes a biotransformation reaction may lead to cleavage of a part of the molecule...

Cytochrome P450 3A4 (CYP3A4), a key enzyme, is pivotal in metabolizing approximately half of the drugs used clinically. The genetic polymorphism of the CYP3A4 gene significantly influences individual variations in drug metabolism, potentially leading to the severe adverse drug reactions (ADRs). In this study, we conducted a genetic analysis on CYP3A4 gene in 1,163 Chinese Han individuals to identify the genetic variations that might affect their drug metabolism capabilities. For this purpose, a multiplex PCR amplicon sequencing technique was developed, enabling us to perform the genotyping of CYP3A4 gene efficiently and economically on a large scale...