Drug Metabolism and Disposition : the Biological Fate of Chemicals

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...

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...

BACKGROUND: Valproic acid (VPA) is a first-line anti-epileptic drug with broad efficacy.Due to significant individual differences in drug metabolism, therapeutic drug monitoring (TDM) is commonly used. However, the conventional therapeutic range (50-100 μg/mL) is inadequate for predicting clinical outcomes.Additionally, the relationship between VPA metabolites and patient outcomes remains unclear.MethodsIn a retrospective study, 485 Chinese Southern Han epilepsy patients treated with VPA as monotherapy were analyzed after reaching steady-state levels...

Coumarin 7'-hydroxylase activity, a specific marker of CYP2A5 activity, and the protein level were measured in liver microsomes of male mice after chronic exposure to e-cigarettes (2.4% nicotine). After exposure for 240 min/day for 5 days, the activity and the protein level in preproenkephalin (ppENK) heterozygous (ppENK (+/-)) mice were significantly elevated ( p< 0.05) compared to the untreated control. This elevation was not due to deletion of the ppENK gene, because the activity did not differ among untreated ppENK (+/-), ppENK (-/-) and wildtype ppENK (+/+) controls...

Detailed structural characterization of small molecule metabolites is desirable during all stages of drug development, and often relies on the synthesis of metabolite standards. However, introducing structural changes into already complex, highly functionalized small molecules both regio- and stereo-selectively can be challenging using approaches that rely purely on synthetic organic chemistry, introducing delays and bottlenecks into the drug development pipeline. An alternative is to use enzymes such as the cytochromes P450 (P450s) that produce the metabolites in vivo, taking advantage of the inherent chirality of the enzyme's active site to achieve regio- and stereoselectivity...

Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small molecule drugs, and therefore may impact the safety and efficacy of medicines in broad therapeutic areas. CYP2D6 is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of CYP2D6 present a unique challenge for academia, industry, and regulatory agencies alike due to the lack of feasibility of characterizing their clinical relevance in clinical trials...

The development of therapeutic fusion protein drugs is often impeded by the unintended consequences that occur from fusing together domains from independent naturally occurring proteins, consequences such as altered biodistribution, tissue uptake or rapid clearance and potential immunogenicity. For therapeutic fusion proteins containing globular domains, we hypothesized that aberrant in vivo behavior could be related to low kinetic stability of these domains leading to local unfolding and susceptibility to partial proteolysis and/or salvage and uptake...

Methadone is cleared predominately by hepatic CYP2B6-catalyzed metabolism to inactive metabolites. CYP2B6 also catalyzes the metabolism of several other drugs. Methadone and CYP2B6 are susceptible to pharmacokinetic drug-drug interactions. Use of natural products such as herbals and other botanicals is substantial and growing, concomitant use of prescription medicines and non-prescription herbals is common and may result in interactions, often precipitated by CYP inhibition. Little is known about herbal product effects on CYP2B6 activity, and CYP2B6-catalyzed methadone metabolism...

Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of CYP3A inhibition (via itraconazole), UGT1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole on days 1-11 and soticlestat 300 mg on day 5 (itraconazole/mefenamic acid study; part 1); mefenamic acid on days 1-7 and soticlestat 300 mg on day 2 (itraconazole/mefenamic acid study; part 2); or rifampin on days 1-13 and soticlestat 300 mg on day 11 (rifampin study)...

Cynomolgus and rhesus macaques are used in drug metabolism studies due to their evolutionary and phylogenetic closeness to humans. Cytochromes P450 (P450s or CYPs), including the CYP2C family enzyme, are important endogenous and exogenous substrate-metabolizing enzymes and play major roles in drug metabolism. In cynomolgus and rhesus macaques, six CYP2Cs have been identified and characterized, namely, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2C76, and CYP2C93. In this study, CYP2C119, a new CYP2C, was identified and characterized in cynomolgus and rhesus macaques...

Dihydrotanshinone I (DHTI) is a pharmacologically active component occurring in the roots of the herbal medicine Salvia miltiorrhiza Bunge. This study investigated DHTI-induced inhibition of CYPs1A1, 1A2 and 1B1, with the aim to determine the potential effects of DHTI on the bioactivation of estradiol (E2), possibly related to preventive/therapeutic strategy for E2-associated breast cancer. Ethoxyresorufin as a specific substrate for CYP1s was incubated with human recombinant CYP1A1, CYP1A2, or CYP1B1 in the presence of DHTI at various concentrations...

Rifampicin (RIF) is a mixed-mode perpetrator that produces pleiotropic effects on liver cytochrome P450 (CYP) enzymes and drug transporters. To assess the complex drug-drug interaction (DDI) liabilities of RIF in vivo , a known probe substrate midazolam (MDZ) along with multiple endogenous biomarkers were simultaneously monitored in beagle dogs before and after a 7-day treatment period by RIF at 20 mg/kg/day. Confirmed by the reduced MDZ plasma exposure and elevated 4β-hydroxycholesterol (4β-HC, biomarker of Cyp3a activities) level, Cyp3a was significantly induced after repeated RIF doses, and such induction persisted for 3 days after cessation of the RIF administration...

Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ), founded an IQ MPS working group in 2014 and Affiliate in 2018...

The utility of PBPK models in support of drug development has been well documented. During the discovery stage, PBPK has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection and early formulation assessment. Previous review articles have proposed model building and application strategies for PBPK-based first in human predictions with comprehensive descriptions of the individual components of PBPK models. This includes the generation of decision trees, based on comprehensive literature reviews, to guide the application of PBPK in the discovery setting...

Ciprofol (HSK3486) is a novel intravenous agent for general anesthesia. In humans, HSK3486 mainly undergoes glucuronidation to form M4 (fraction of clearance [fCL ]: 62.6%), followed by the formation of mono-hydroxylated metabolites that further undergo glucuronidation and sulfation to produce M5-1, M5-2, M5-3, and M3 (summed fCL : 35.2%). However, the complete metabolic pathways of HSK3486 in humans remain unclear. In this study, by comparison with chemically synthesized reference standards， three mono-hydroxylated metabolites (M7-1, 4-hydroxylation with an unbound intrinsic clearance [CLint,u ] of 2211 μL/min/mg; M7-2, ω-hydroxylation with a CLint,u of 600 μL/min/mg, and M7-3, (ω-1)-hydroxylation with a CLint,u of 78...