Mechanistic and Quantitative Understanding of Pharmacokinetics in Zebrafish Larvae through Nanoscale Blood Sampling and Metabolite Modeling of Paracetamol

The Journal of Pharmacology and Experimental Therapeutics
Rob C van WijkPiet H van der Graaf

Abstract

Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically studied and quantified pharmacokinetics in zebrafish larvae, and compared this to higher vertebrates, using paracetamol (acetaminophen) as a paradigm compound. A method was developed to sample blood from zebrafish larvae 5 days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulfate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analyzed through nonlinear mixed-effects modeling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein, with a median volume (interquartile range) of 1...Continue Reading

References

Apr 1, 1987·Clinical Pharmacology and Therapeutics·J T SlatteryS D Nelson
Jul 1, 1996·Toxicology and Applied Pharmacology·L Liu, C D Klaassen
Dec 1, 1995·Journal of Pharmacokinetics and Biopharmaceutics·M O KarlssonL B Sheiner
Jan 5, 2002·Journal of Pharmacokinetics and Pharmacodynamics·S L Beal
Jul 31, 2003·Journal of Veterinary Pharmacology and Therapeutics·K JanusZ Muszczynski
Feb 3, 2005·Nature Reviews. Drug Discovery·Leonard I Zon, Randall T Peterson
Jul 19, 2005·Computer Methods and Programs in Biomedicine·Lars LindbomNiclas Jonsson
Sep 2, 2008·Clinical and Experimental Pharmacology & Physiology·David ReithMathew Zacharias
Jul 16, 2010·Computer Methods and Programs in Biomedicine·Ron J KeizerAlwin D R Huitema
Dec 27, 2011·Biomedical Research·Izumi YamasakiYasuhiko Yamada
Mar 28, 2012·The Journal of Biological Chemistry·Johannes van den BoomJonathan W Mueller
Jun 30, 2012·Nature Methods·Johannes SchindelinAlbert Cardona
Jul 19, 2012·Biopharmaceutics & Drug Disposition·Soo Hyun LeeByung Hwa Jung
Apr 23, 2013·Environmental Toxicology and Chemistry·Agnes KühnertEberhard Küster
Jun 19, 2013·Methods : a Companion to Methods in Enzymology·Herman P SpainkRon P Dirks
May 23, 2014·Journal of Pharmacokinetics and Pharmacodynamics·Katie H OwensDavid M Reith
Jul 4, 2015·European Journal of Clinical Pharmacology·Elke H J KrekelsCatherijne A J Knibbe
Aug 28, 2015·Nature Protocols·Takashi FujiiTsutomu Masujima
Sep 9, 2015·Journal of Theoretical Biology·Dennis ReddyhoffSteven Webb
Sep 12, 2015·Nature Reviews. Drug Discovery·Calum A MacRae, Randall T Peterson
Jan 29, 2016·Clinical Pharmacokinetics·Anne van RongenCatherijne A J Knibbe
Nov 25, 2016·CPT: Pharmacometrics & Systems Pharmacology·T H T NguyenUNKNOWN Model Evaluation Group of the International Society of Pharmacometrics (ISoP) Best Practice Committee
Mar 25, 2018·Clinical Pharmacokinetics·Sebastiaan C GouloozeCatherijne A J Knibbe
Apr 26, 2018·CPT: Pharmacometrics & Systems Pharmacology·Pascal SchulthessPiet H van der Graaf
Jan 8, 2019·PloS One·Maria Lorena Cordero-MaldonadoJan de Sonneville
Feb 17, 2019·Scientific Reports·Rob C van WijkHerman P Spaink

❮ Previous
Next ❯

Citations

Aug 30, 2020·British Journal of Pharmacology·Rob C van WijkElke H J Krekels
Jun 13, 2021·Nature Reviews. Drug Discovery·E Elizabeth PattonDavid M Langenau

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.