-
The AAPS Journal Mar 2015As a result of high-throughput ADME screening, early metabolite identification, and exploration of novel chemical entities, low-intrinsic-clearance compounds continue to... (Review)
Review
As a result of high-throughput ADME screening, early metabolite identification, and exploration of novel chemical entities, low-intrinsic-clearance compounds continue to increase in drug discovery portfolios. Currently available in vitro tools have limited resolution below a certain intrinsic clearance value, which can lead to overestimation of clearance and dose and underestimation of half-life. Significant advances have been made in recent years and novel approaches have been developed to address the challenges of low clearance in drug discovery, such as the hepatocyte relay method, use of qNMR-based standards of biosynthesized drug metabolites to permit monitoring metabolite formation, coculture hepatocyte systems, and the time depending modeling approach. Future development in the field will enable faster, more precise, and lower cost profiling of the properties of low-clearance compounds for intrinsic clearance, metabolite identification, and reaction phenotyping.
Topics: Animals; Coculture Techniques; Drug Design; Drug Discovery; Half-Life; Hepatocytes; High-Throughput Screening Assays; Humans; Magnetic Resonance Spectroscopy; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 25567366
DOI: 10.1208/s12248-014-9691-7 -
Current Drug Metabolism 2023Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene... (Review)
Review
Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene expression or function may alter the pharmacokinetics/ pharmacodynamics (PK/PD) and further influence drug safety and therapeutic outcomes. ADME gene functions are controlled by diverse factors, such as genetic polymorphism, transcriptional regulation, and coadministered medications. MicroRNAs (miRNAs) are a superfamily of regulatory small noncoding RNAs that are transcribed from the genome to regulate target gene expression at the post-transcriptional level. The roles of miRNAs in controlling ADME gene expression have been demonstrated, and such miRNAs may consequently influence cellular drug metabolism and disposition capacity. Several types of miRNA mimics and small interfering RNA (siRNA) reagents have been developed and widely used for ADME research. In this review article, we first provide a brief introduction to the mechanistic actions of miRNAs in post-transcriptional gene regulation of drug-metabolizing enzymes, transporters, and transcription factors. After summarizing conventional small RNA production methods, we highlight the latest advances in novel recombinant RNA technologies and applications of the resultant bioengineered RNA (BioRNA) agents to ADME studies. BioRNAs produced in living cells are not only powerful tools for general biological and biomedical research but also potential therapeutic agents amenable to clinical investigations.
Topics: Humans; Gene Expression Regulation; MicroRNAs; Inactivation, Metabolic
PubMed: 37170982
DOI: 10.2174/1389200224666230425232433 -
CPT: Pharmacometrics & Systems... Aug 2020The human radiolabeled absorption, distribution, metabolism, and excretion (ADME) study offers a quantitative and comprehensive overall picture of the disposition of a... (Review)
Review
The human radiolabeled absorption, distribution, metabolism, and excretion (ADME) study offers a quantitative and comprehensive overall picture of the disposition of a drug, including excretion pattern and metabolite profiles in circulation and excreta. The data gathered from the ADME study are highly informative for developing a cohesive strategy for clinical pharmacology studies. Elements of standard ADME study designs are described. An exciting new development in human ADME studies is the application of accelerator mass spectrometry (AMS) as the detection technique for carbon-14, in replacement of radioactivity measurements. This technology permits administration of 100-fold to 1,000-fold lower amounts of carbon-14, and thus opens the door to the application of new study designs. A new ADME study design, termed the AMS-Enabled Human ADME study, is described. In this design, both oral and intravenous administration are assessed in a single clinical study with a two-period crossover. In addition to all of the standard ADME study end points (e.g., mass balance and quantitative metabolite profiles), the AMS-Enabled ADME study can provide the fundamental pharmacokinetic parameters of clearance, volume of distribution, absolute oral bioavailability, and even estimates of the fraction of the dose absorbed. Thus, we have entered a new era of human ADME study design that can yield vastly more informative and complete data sets enabling a superior understanding of overall drug disposition.
Topics: Administration, Intravenous; Administration, Oral; Animals; Biological Availability; Carbon Radioisotopes; Humans; Mass Spectrometry; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology
PubMed: 32562380
DOI: 10.1002/psp4.12540 -
Drug Metabolism and Pharmacokinetics 2012In this review, novel aspects of the role of esterases, which contribute to the metabolism of 10% of therapeutic drugs, are described. Esterases hydrolyze the compounds... (Review)
Review
In this review, novel aspects of the role of esterases, which contribute to the metabolism of 10% of therapeutic drugs, are described. Esterases hydrolyze the compounds that contain ester, amide, and thioester bonds, which cause prodrug activation or detoxification. Among esterases, carboxylesterases are well known to be involved in the hydrolysis of a variety of drugs. Additionally, other esterases have recently received attention for their pharmacological and toxicological roles. Arylacetamide deacetylase (AADAC) is involved in the hydrolysis of flutamide, phenacetin, and rifamycins. AADAC is associated with adverse drug reactions because the hydrolytic metabolites of flutamide and phenacetin appear to be associated with hepatotoxicity and nephrotoxicity/hematotoxicity, respectively. Paraoxonase and butyrylcholinesterase hydrolyze pirocarpine/simvastatin and succinylcholine/bambuterol, respectively. Although the esterases that hydrolyze the acyl-glucuronides of drugs have largely been unknown, we recently found that α/β hydrolase domain containing 10 (ABHD10) is responsible for the hydrolysis of mycophenolic acid acyl-glucuronide in human liver. Because acyl-glucuronides are associated with toxicity, ABHD10 might function as a detoxification enzyme. Thus, various esterases, which include enzymes that have not been known to hydrolyze drugs, are involved in drug metabolism with different substrate specificity. Further esterase studies should be conducted to promote our understanding in clinical pharmacotherapy and drug development.
Topics: Animals; Esterases; Humans; Hydrolysis; Inactivation, Metabolic; Pharmacokinetics; Prodrugs
PubMed: 22813719
DOI: 10.2133/dmpk.dmpk-12-rv-042 -
International Journal of Molecular... Apr 2023Lipophilicity is one of the key properties of a potential drug that determines the solubility, the ability to penetrate through cell barriers, and transport to the...
Lipophilicity is one of the key properties of a potential drug that determines the solubility, the ability to penetrate through cell barriers, and transport to the molecular target. It affects pharmacokinetic processes such as adsorption, distribution, metabolism, excretion (ADME). The 10-substituted 1,9-diazaphenothiazines show promising if not impressive in vitro anticancer potential, which is associated with the activation of the mitochondrial apoptosis pathway connected with to induction BAX, forming a channel in MOMP and releasing cytochrome c for the activation of caspases 9 and 3. In this publication, the lipophilicity of previously obtained 1,9-diazaphenothiazines was determined theoretically using various computer programs and experimentally using reverse-phase thin-layer chromatography (RP-TLC) and a standard curve. The study presents other physicochemical, pharmacokinetic, and toxicological properties affecting the bioavailability of the test compounds. ADME analysis was determined in silico using the SwissADME server. Molecular targets studies were identified in silico using the SwissTargetPrediction server. Lipinski's rule of five, Ghose's, and Veber's rules were checked for the tested compounds, confirming their bioavailability.
Topics: Adsorption; Chromatography, Reverse-Phase; Biological Availability
PubMed: 37108135
DOI: 10.3390/ijms24086970 -
British Journal of Pharmacology Jun 2015The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is... (Review)
Review
The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non-coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high-throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine.
Topics: Absorption, Physiological; Biotransformation; Cytochrome P-450 Enzyme System; DNA Methylation; Gene Expression Regulation; Humans; Membrane Transport Proteins; MicroRNAs; Pharmaceutical Preparations; Receptors, Cytoplasmic and Nuclear; Transcriptome
PubMed: 25296724
DOI: 10.1111/bph.12968 -
British Journal of Clinical Pharmacology Dec 19961. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively... (Review)
Review
1. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively low levels of systemic absorption. 2. Pharmacokinetic evaluation of drug absorption from the lungs provides an accurate and reproducible method for comparing different inhaler delivery systems, as well as for evaluating bioequivalence of generic drug formulations. 3. The measurement of drug absorption from the lungs may also be applied to assess the effects of inhalation technique on drug delivery in vivo. For example with salbutamol delivered via a large volume spacer, lung bioavailability has been shown to be altered by factors such as the number of actuated puffs, inhalation-actuation delay and washing procedure. 4. Differences in drug delivery to the lungs between dry powder reservoir and pressurised metered-dose aerosol devices translate directly into commensurate differences in clinical efficacy for delivery of both inhaled beta 2-adrenoceptor agonists and corticosteroids. 5. For inhaled corticosteroids, pharmacokinetic evaluation using oral charcoal to obviate alimentary absorption may be applied to quantify the relative gut and lung components of systemic bioavailability. In tandem with information on receptor potency and affinity, drug elimination and distribution, these data may help in part to explain observed differences between different inhaled corticosteroids in terms of their systemic bioactivity profiles. 6. Studies are required to evaluate whether pharmacokinetic evaluation of lung absorption is a suitable way of quantifying delivery of nebulised aminoglycoside antibiotics, as for example in patients with cystic fibrosis. 7. Pharmacokinetic evaluation appears to have an established role in the quantification of drug delivery to the lungs and provides important information which is complimentary to other techniques such as radiolabelled deposition. The next decade of research into pharmacokinetics of established and novel drugs and delivery systems is awaited with keen interest, and will hopefully provide a greater understanding into ways of optimising the benefit-risk ratio for inhaled drugs.
Topics: Administration, Inhalation; Biological Availability; Humans; Lung; Pharmacokinetics
PubMed: 8971424
DOI: 10.1046/j.1365-2125.1996.00493.x -
Drug Metabolism Reviews Aug 2022Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by... (Review)
Review
Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).
Topics: Biotransformation; Drug Discovery; Humans; Inactivation, Metabolic
PubMed: 35815654
DOI: 10.1080/03602532.2022.2097253 -
Alimentary Pharmacology & Therapeutics Sep 2014Obesity surgery is acknowledged as a highly effective therapy for morbidly obese patients. Beneficial short-term effects on common comorbidities are practically... (Review)
Review
BACKGROUND
Obesity surgery is acknowledged as a highly effective therapy for morbidly obese patients. Beneficial short-term effects on common comorbidities are practically undisputed, but a growing data pool from long-term follow-up reveals increasing evidence of potentially severe nutritional and pharmacological consequences.
AIMS
To assess the prevalence, causes and symptoms of complications after obesity surgery, to elucidate and compare therapy recommendations for macro- and micronutrient deficiencies, and to explore surgically-induced effects on drug absorption and bioavailability, discussing ramifications for long-term therapy and prophylaxis.
METHODS
PubMed, Embase and MEDLINE were searched using terms including, but not limited to, bariatric surgery, gastric bypass, obesity surgery and Roux-en-Y, coupled with secondary search terms, e.g. anaemia, micronutrients, vitamin deficiency, bacterial overgrowth, drug absorption, pharmacokinetics, undernutrition. All studies in English, French or German published January 1980 through March 2014 were included.
RESULTS
Macro- and micronutrient deficiencies are common after obesity surgery. The most critical, depending on surgical technique, are hypoalbuminemia (3-18%) and deficiencies of vitamins B1 (≤49%), B12 (19-35%) and D (25-73%), iron (17-45%) and zinc (12-91%). Many drugs commonly administered to obese patients (e.g. anti-depressants, anti-microbials, metformin) are subject to post-operative and/or PPI-associated changes affecting bioavailability and absorption.
CONCLUSIONS
Complications are associated with pre-operative and/or post-operative malnutrition or procedure-related changes in intake, absorption and drug bioavailability. The high prevalence of nutrient deficiencies after obesity surgery makes life-long nutritional monitoring and supplementation essential. Post-operative changes to drug absorption and bioavailability in bariatric patients cast doubt on the validity of standard drug dosage and administration recommendations.
Topics: Bariatric Surgery; Biological Availability; Deficiency Diseases; Humans; Hypoalbuminemia; Obesity, Morbid; Pharmaceutical Preparations; Pharmacokinetics; Postoperative Complications
PubMed: 25078533
DOI: 10.1111/apt.12872 -
Annals of Medicine Aug 1991The increasing popularity of sporting events, even for people on drug treatment, has raised the question of the interaction of exercise and pharmacokinetics. Exercise... (Review)
Review
The increasing popularity of sporting events, even for people on drug treatment, has raised the question of the interaction of exercise and pharmacokinetics. Exercise reduces splanchnic blood flow, but possible changes in the absorption of orally given drugs seem to be of minor clinical significance. Absorption from intramuscular, subcutaneou and transdermal application sites may be accelerated by exercise, possibly causing harmful consequences, e.g. in diabetics treated with insulin. Exercise or physical work increases the rate and depth of respiration thus increasing alveolar exchange of gases and vapours. Physical activity increases muscular blood flow and the binding of digoxin to muscular structures, with a simultaneous fall in the concentration of serum digoxin. Reduction in blood flow to adipose and other inactive tissues may delay the distribution of some drugs that are stored or removed by these tissues. The change from supine to upright position can affect the distribution of a drug. Exercise reduces the blood flow in the liver and deactivation of drugs with flow-limited (high clearance) hepatic metabolism such as nitrates and lidocaine. Metabolism of capacity-limited (low clearance) drugs, e.g. antipyrine, diazepam and amobarbital, is not influenced by exercise. Renal plasma flow, urine excretion rate and urine pH are also reduced by exercise. This is an important reason why the serum levels of drugs eliminated through the kidneys increase during physical stress. The changes in parenteral absorption and distribution volume of some drugs caused by exercise, as well as the short half-life of drugs, are properties resulting in altered therapeutic/toxic response in those drugs with a narrow therapeutic range.
Topics: Exercise; Humans; Pharmacokinetics
PubMed: 1930919
DOI: 10.3109/07853899109148062