David Dahlgren

Effects of intestinal permeation enhancers on solubilization and epithelial transport of the proteolysis targeting chimera (PROTAC) ARV-471 in rats

Janis Niessen, Mirko Koziolek, Thomas B. Borchardt, Anura S. Indulkar et autres

The molecular properties of proteolysis targeting chimeras (PROTACs) often fall outside the ‘drug-like’ rule of five (Ro5) chemical space, associated with poor intestinal solubility, permeability, and absorption. While formulation strategies have primarily focused on solubility enhancement, the intrinsic permeability barriers of PROTACs …

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Characterization of hepatocellular carcinoma patient-derived organoids from patients receiving transarterial chemoembolization as a model for preclinical drug response assessment

Jaafar Khaled, Sofi Sennefelt Nyman, David Dahlgren, Fredrik Rorsman et autres

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and is often diagnosed at an intermediate stage in patients with chronic liver disease. Transarterial chemoembolization (TACE) is the first-line treatment in this setting. However, drug response remains variable and …

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Column coupling for chiral LC-MS separation resolves triacylglycerol enantiomers and regioisomers in complex samples without flow recycling

Jenny M. Nilsson, David Balgoma, Edvin Stephansson, Sofia Landström et autres

The positional distribution of fatty acids in the glycerol of triacylglycerols (TGs) gives multiple regioisomeric and enantiomeric species with different absorption, metabolism and tissue distribution. This diversity is further enhanced by the positional isomers of double bonds in these fatty acids which …

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The In Vivo Effect of Amorphous Drug Nanoprecipitates on the Intestinal Absorption of the PROTACs ARV-110 (Bavdeglutamide) and ARV-471 (Vepdegestrant)

Janis Niessen, Mirko Koziolek, Anura Indulkar, Thomas B. Borchardt et autres

Targeted degradation of disease-associated proteins via proteolysis-targeting chimeras (PROTACs) is a powerful pharmacological strategy, but it requires a complex molecular architecture associated with poor intestinal absorption. Rational development of orally bioavailable PROTACs requires a thorough understanding of their biopharmaceutical properties. This mechanistic …

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Letter to the Editor Regarding “The Effect of Itraconazole on the Pharmacokinetics of Vepdegestrant, a PROteolysis TArgeting Chimera Estrogen Receptor Degrader, in Healthy Adult Participants” Recently Published by Tran and Colleagues

Janis Niessen, Hans Lennernäs, David Dahlgren

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Chiral LC-MS separation resolves TG enantiomers and regioisomers in complex samples without flow recycling

Jenny M. Nilsson, David Balgoma, Edvin Stephansson, Sofia Landström et autres

A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats

Janis Niessen, Nathalie Arendt, Markus Sjöblom, Ilse R. Dubbelboer et autres

• The intestinal effective permeability was moderate for ARV-110 and low for ARV-471 in rats. • Intestinal P-gp contributes to limited intestinal permeability of ARV-110 and ARV-471. • CYP3A seems to play minor role in first-pass metabolism of ARV-110 and ARV-471. • …

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A Comprehensive Mechanistic Investigation of Factors Affecting Intestinal Absorption and Bioavailability of Two Protacs in Rats

Janis Niessen, Nathalie Arendt, Markus Sjöblom, Ilse R. Dubbelboer et autres

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Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids

Karsten Peters, Ada Lerma Clavero, Fredrik Kullenberg, Maria Kopsida et autres

Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the …

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Development and validation of LC-MS/MS methods for the pharmacokinetic assessment of the PROTACs bavdeglutamide (ARV-110) and vepdegestrant (ARV-471)

Janis Niessen, Jenny M. Nilsson, Karsten Peters, Anura Indulkar et autres

Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. …

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Development and Validation of Lc-Ms/Ms Methods for the Pharmacokinetic Assessment of the Protacs Bavdeglutamide (Arv-110) and Vepdegestrant (Arv-471)

Janis Niessen, Jenny M. Nilsson, Karsten Peters, Anura Indulkar et autres

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Medicinal grade opium tincture for severe diarrhea: effect revisited in observational study

David Dahlgren, Per M. Hellström

PURPOSE OF REVIEW: Chronic diarrhea is a common disorder that interferes with normal daily activities and results in poor quality of life. Fecal urgency and incontinence often necessitate clinical consultation, but the pathophysiological mechanisms are difficult to differentiate in a clinical setting. …

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