Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Helena Anna ThörnHans Lennernäs

Abstract

In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4'-β-glucuronide (R-4-G). Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E(G)) during first-pass to more than 70% and a high concentration (AUC(0-6 h) ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E(H)) of raloxifene was ~50% and as in humans the bioavailability become low (~7%) in pigs. Interestingly the E(H) of raloxifene and R-4-G was time-dependent after i.j. administration. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.

References

Jan 1, 1980·The Journal of Pharmacy and Pharmacology·M K Cassidy, J B Houston
Jan 1, 1996·European Journal of Clinical Pharmacology·A A RaoofR K Verbeeck
Dec 10, 1999·Transplantation·M DesilleB Clément
Dec 12, 2001·British Journal of Clinical Pharmacology·K Bowalgaha, J O Miners
May 23, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Daniel C KempJeffrey C Stevens
Nov 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuichiro WatanabeTsuyoshi Yokoi
Dec 9, 2003·Research in Veterinary Science·B SzotákováL Skálová
Mar 17, 2004·The Journal of Pharmacology and Experimental Therapeutics·Eun Ju JeongMing Hu
Jul 20, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Olivier Bernard, Chantal Guillemette
Mar 17, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eun Ju JeongMing Hu
Apr 20, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Niclas PetriHans Lennernäs
Jun 1, 2007·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Jurij TronteljAles Mrhar
Feb 3, 2009·Pharmaceutical Research·Helen E CubittAleksandra Galetin
Feb 10, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Helen E CubittAleksandra Galetin
Mar 31, 2011·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Helena Anna ThörnHans Lennernäs
Jun 8, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keigo KosakaToshiyuki Kume
Jul 15, 2011·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Tina TrdanAleš Mrhar
Aug 6, 2011·The AAPS Journal·Leslie Z BenetTudor I Oprea

❮ Previous
Next ❯

Citations

Nov 28, 2012·Pharmaceutical Research·Claudia Suenderhauf, Neil Parrott
Jan 1, 2014·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Punna Rao RaviRahul Vats
Dec 11, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Anna LundahlMikael Hedeland
Mar 19, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Erik SjögrenPeter Langguth
Mar 5, 2020·Drug Development and Industrial Pharmacy·Huixin LiTianhong Zhang
Feb 16, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Rebecca DargueIan D Wilson
Jan 12, 2021·Toxicology Letters·Viktoriia BurkinaMartin Krøyer Rasmussen

❮ 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.