Drug Dissolution in Oral Drug Absorption: Workshop Report.

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk.

PBPK Modeling of PAXLOVID: Incorporating Rotamer Conversion Kinetics to Advanced Dissolution and Absorption Model.

PAXLOVID™ is a combination medicine of nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV2 main protease (M), developed for the treatment of COVID-19. Ritonavir is co-administered as a pharmacokinetics (PK) enhancer to inhibit CYP3A mediated metabolism increasing exposures of nirmatrelvir.

Self-Assembly Properties of an Amphiphilic Phosphate Ester Prodrug Designed for the Treatment of COVID-19.

PF-07304814 is a water-soluble phosphate ester prodrug of a small molecule inhibitor for the SARS CoV-2 3CL protease designed for the treatment of COVID-19. The amphiphilicity and self-assembly behavior of the prodrug was investigated computationally and experimentally via multiple orthogonal techniques to better design formulations for intravenous infusion. The self-assembly of PF-07304814 into micellar structures enabled an increase in the solubility of lipophilic impurities by up to 1900x in clinically relevant formulations.

Physiologically-Based Pharmacokinetic Modeling of PAXLOVID™ with First-Order Absorption Kinetics.

Purpose: PAXLOVID™ is nirmatrelvir tablets co-packaged with ritonavir tablets. Ritonavir is used as a pharmacokinetics (PK) enhancer to reduce metabolism and increase exposure of nirmatrelvir. This is the first disclosure of Paxlovid physiologically-based pharmacokinetic (PBPK) model.

Dynamic modeling of subcellular phenylpropanoid metabolism in Arabidopsis lignifying cells.

Lignin is a polymer that significantly inhibits saccharification of plant feedstocks. Adjusting the composition or reducing the total lignin content have both been demonstrated to result in an increase in sugar yield from biomass. However, because lignin is essential for plant growth, it cannot be manipulated with impunity.

A C isotope labeling method for the measurement of lignin metabolic flux in Arabidopsis stems.

Background: Metabolic fluxes represent the functional phenotypes of biochemical pathways and are essential to reveal the distribution of precursors among metabolic networks. Although analysis of metabolic fluxes, facilitated by stable isotope labeling and mass spectrometry detection, has been applied in the studies of plant metabolism, we lack experimental measurements for carbon flux towards lignin, one of the most abundant polymers in nature.

Results: We developed a feeding strategy of excised Arabidopsis stems with C labeled phenylalanine (Phe) for the analysis of lignin biosynthetic flux.

Multifaceted plant responses to circumvent Phe hyperaccumulation by downregulation of flux through the shikimate pathway and by vacuolar Phe sequestration.

Detrimental effects of hyperaccumulation of the aromatic amino acid phenylalanine (Phe) in animals, known as phenylketonuria, are mitigated by excretion of Phe derivatives; however, how plants endure Phe accumulating conditions in the absence of an excretion system is currently unknown. To achieve Phe hyperaccumulation in a plant system, we simultaneously decreased in petunia flowers expression of all three Phe ammonia lyase (PAL) isoforms that catalyze the non-oxidative deamination of Phe to trans-cinnamic acid, the committed step for the major pathway of Phe metabolism. A total decrease in PAL activity by 81-94% led to an 18-fold expansion of the internal Phe pool.

Targeted Metabolomics of the Phenylpropanoid Pathway in Arabidopsis thaliana using Reversed Phase Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Introduction: The phenylpropanoid pathway is a source of a diverse group of compounds derived from phenylalanine, many of which are involved in lignin biosynthesis and serve as precursors for the production of valuable compounds, such as coumarins, flavonoids, and lignans. Consequently, recent efforts have been invested in mechanistically understanding monolignol biosynthesis, making the quantification of these metabolites vital.

Objective: To develop an improved and comprehensive analytical method for (i) extensively profiling, and (ii) accurately quantifiying intermediates of the monolignol biosynthetic network, using Arabidopsis thaliana as a model system.

Identification of a plastidial phenylalanine exporter that influences flux distribution through the phenylalanine biosynthetic network.

In addition to proteins, L-phenylalanine is a versatile precursor for thousands of plant metabolites. Production of phenylalanine-derived compounds is a complex multi-compartmental process using phenylalanine synthesized predominantly in plastids as precursor. The transporter(s) exporting phenylalanine from plastids, however, remains unknown.

Rethinking how volatiles are released from plant cells.

For plant volatile organic compounds (VOCs) to be emitted, they must cross membrane(s), the aqueous cell wall, and sometimes the cuticle, before moving into the gas phase. It is presumed that VOC movement through each barrier occurs via passive diffusion. However, VOCs, which are primarily nonpolar compounds, will preferentially partition into membranes, making diffusion into aqueous compartments slow.