Human absorption, distribution, metabolism, and excretion (hADME) studies represent one of the most important clinical studies in terms of obtaining a comprehensive and quantitative overview of the total disposition of a drug. This article will provide background on the origins of hADME studies as well as provide an overview of technological innovations that have impacted how hADME studies are carried out and analyzed. An overview of the current state of the art for hADME studies will be provided, the impacts of advances in technology and instrumentation on the timing of and approaches to hADME studies will be discussed, and a summary of the parameters and information obtained from these studies will be offered. Additionally, aspects of the ongoing debate over the importance of animal absorption, distribution, metabolism, and excretion studies versus a "human-first, human-only strategy" will be presented. Along with the information above, this manuscript will highlight how, for over 50 years, has served as an important outlet for the reporting of hADME studies. SIGNIFICANCE STATEMENT: Human absorption, distribution, metabolism, and excretion (hADME) studies have and will continue to be important to the understanding and development of drugs. This manuscript provides a historical perspective on the origins of hADME studies as well as advancements resulting in the current-state-of the art practice for these studies.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1124/dmd.122.001006 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Human Absorption, Distribution, Metabolism, and Excretion Studies: Origins, Innovations, and Importance.
Drug Metab Dispos
June 2023
Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc., Groton, Connecticut.
Human absorption, distribution, metabolism, and excretion (hADME) studies represent one of the most important clinical studies in terms of obtaining a comprehensive and quantitative overview of the total disposition of a drug. This article will provide background on the origins of hADME studies as well as provide an overview of technological innovations that have impacted how hADME studies are carried out and analyzed. An overview of the current state of the art for hADME studies will be provided, the impacts of advances in technology and instrumentation on the timing of and approaches to hADME studies will be discussed, and a summary of the parameters and information obtained from these studies will be offered.
View Article and Find Full Text PDFApplication of Accelerator Mass Spectrometry to Characterize the Mass Balance Recovery and Disposition of AZD4831, a Novel Myeloperoxidase Inhibitor, following Administration of an Oral Radiolabeled Microtracer Dose in Humans.
Drug Metab Dispos
April 2023
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)
This study evaluated the mass balance and disposition of AZD4831, a novel myeloperoxidase inhibitor, in six healthy participants using a C-labeled microtracer coupled with analysis by accelerator mass spectrometry (AMS). A single oral dose of 10 mg C-AZD4831 (14.8 kBq) was administered as a solution, and C levels were quantified by AMS in blood, urine, and feces over 336 hours postdose.
View Article and Find Full Text PDFConsiderations for Human ADME Strategy and Design Paradigm Shift(s) - An Industry White Paper.
Clin Pharmacol Ther
April 2023
Sanofi, Montpellier, Occitanie, France.
The human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of the clinical pharmacology package for small molecule drugs, providing comprehensive information on the rates and routes of disposition and elimination of drug-related material in humans through the use of C-labeled drug. Significant changes have already been made in the design of the hADME study for many companies, but opportunity exists to continue to re-think both the design and timing of the hADME study in light of the potential offered by newer technologies, that enable flexibility in particular to reducing the magnitude of the radioactive dose used. This paper provides considerations on the variety of current strategies that exist across a number of pharmaceutical companies and on some of the ongoing debates around a potential move to the so called "human first/human only" approach, already adopted by at least one company.
View Article and Find Full Text PDFProduction of 12-hydroxy dodecanoic acid methyl ester using a signal peptide sequence-optimized transporter AlkL and a novel monooxygenase.
Bioresour Technol
November 2019
Interdisciplinary Program of Bioengineering, Seoul National University, Seoul 08826, Republic of Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea; School of Chemical and Biological Engineering, Seoul National University, Seoul, Republic of Korea; Institute of Engineering Research, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:
Article Synopsis
- The study replaced the signal peptide of AlkL with other options to boost its ability to transport dodecanoic acid methyl ester (DAME) into E. coli, finding that the FadL signal peptide improved transport activity.
- Promoter optimization enhanced the heterologous expression of AlkL and the alkane monooxygenase system (AlkBGT), leading to greater ω-oxygenation activity.
- Bioinformatics identified a new monooxygenase from Pseudomonas pelagia with 20% higher activity towards DAME, and combining this with a chimeric transporter yielded significant production of 12-hydroxy dodecanoic acid methyl ester (HADME) and dodecanedioic acid mon
Evaluation of cAMS for C microtracer ADME studies: opportunities to change the current drug development paradigm.
Bioanalysis
March 2018
Novartis Pharma AG, Novartis Institutes for Biomedical Research, PK Sciences, Fabrikstrasse 14, CH-4002 Basel, Switzerland.
Aim: Although regulatory guidances require human metabolism information of drug candidates early in the development process, the human mass balance study (or hADME study), is performed relatively late. hADME studies typically involve the administration of a C-radiolabelled drug where biological samples are measured by conventional scintillation counting analysis. Another approach is the administration of therapeutic doses containing a C-microtracer followed by accelerator mass spectrometry (AMS) analysis, enabling hADME studies completion much earlier.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!