Determination of a human hepatic microsomal scaling factor for predicting in vivo drug clearance

Pharmaceutical Research
Nancy HakoozJ Brian Houston

Abstract

To determine a microsomal scaling factor for human liver suitable for prediction of in vivo drug clearance from in vitro data and to explore the role of inter-liver variability in this factor on the reported underprediction from microsomal parameters. Cytochrome P450 (henceforth P450) content in whole homogenates and microsomes from 38 donor livers was used to determine a microsomal scaling factor. In a subset (n = 20) of these preparations, individual P450 enzymes were examined by Western blotting and selective probe activities were determined. The scaling factor from 38 livers averaged 40 mg microsomal protein per gram liver with a coefficient of variation of 31%. Western blotting experiments indicated that there was no P450 enzyme-specific trend in the distribution of individual P450 enzymes in liver microsomes relative to whole homogenate. Predictions based on an average scaling factor resulted in a satisfactory prediction of intrinsic clearance of three benzodiazepines similar to that obtained using individual factors for the same livers. A value for human liver microsomal scaling of 40 mg microsomal protein per gram liver has been established. The reason for underprediction previously reported for 52 different drug substr...Continue Reading

References

Oct 1, 1990·Clinical Pharmacology and Therapeutics·D L SchmuckerP Kremers
Aug 1, 1986·Acta Pharmacologica Et Toxicologica·C BäärnhielmI Skånberg
Jun 1, 1980·Clinical Pharmacology and Therapeutics·C von BahrH Glaumann
Jul 15, 1996·Archives of Biochemistry and Biophysics·R E PearceA Parkinson
Jan 1, 1997·Pharmacology & Therapeutics·T IwatsuboY Sugiyama
Jan 9, 1998·Drug Metabolism Reviews·J B Houston, D J Carlile
Dec 16, 1998·Toxicology and Applied Pharmacology·J C LipscombJ Z Byczkowski
Jun 26, 1999·British Journal of Clinical Pharmacology·D J CarlileJ B Houston
Feb 21, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ivan NestorovMalcolm Rowland
Sep 13, 2003·British Journal of Clinical Pharmacology·Z E WilsonG T Tucker
Sep 30, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·H C RawdenJ B Houston
Nov 30, 2005·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Trevor N JohnsonAmin Rostami-Hodjegan
Jan 1, 2003·Toxicology Mechanisms and Methods·John C LipscombJohn E Snawder

❮ Previous
Next ❯

Citations

Nov 17, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Lena ErnstgårdGunnar Johanson
Apr 12, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shogo J MiyagiAbby C Collier
Nov 22, 2007·Expert Opinion on Drug Metabolism & Toxicology·Stefan S De Buck, Claire E Mackie
Oct 31, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·O Pelkonen, M Turpeinen
Oct 15, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·R StringerJ B Houston
Mar 5, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Maria RosaHugues Chanteux
Jul 20, 2007·The Journal of Pharmacy and Pharmacology·Urban Fagerholm
Mar 20, 2014·Biopharmaceutics & Drug Disposition·Lies De BockJan Van Bocxlaer
Apr 5, 2014·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Rowan A StringerBindi Sohal
Jul 19, 2014·Pharmaceutical Research·Aki T HeikkinenNeil Parrott
Oct 10, 2009·Integrative Cancer Therapies·Stacy S ShordAlvina Lukose
Dec 5, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Khaled A ShibanyStuart W Paine
Feb 3, 2007·Nature Reviews. Drug Discovery·Amin Rostami-Hodjegan, Geoffrey T Tucker
Dec 14, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Francesca L WoodDavid Hallifax
Feb 7, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Rowan A StringerJ Brian Houston
Mar 27, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuki KobayashiTsuyoshi Yokoi
Jan 30, 2007·The Journal of Pharmacology and Experimental Therapeutics·Rheem A TotahEvan D Kharasch
Mar 13, 2009·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S ChoiH Jeong
Nov 30, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hayley S BrownJ Brian Houston
Feb 23, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiaohua ZhaoLing Yang
Aug 12, 2018·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·C M Bowman, L Z Benet
Mar 26, 2021·Journal of Medicinal Chemistry·Jasleen K Sodhi, Leslie Z Benet
May 14, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Areti-Maria VasilogianniAmin Rostami-Hodjegan
Aug 19, 2021·Drug Metabolism Reviews·Siva Nageswara Rao GajulaRajesh Sonti
Oct 27, 2020·Analytical Chemistry·Gowtham SathyanarayananTiina Sikanen

❮ 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.