Drugs and Pharmacogenetics - Drug Discovery Digest

Integrating pharmacogenetics data: a new lens for target prioritisation

The Open Targets Blog

MAY 9, 2024

In December 2023, we introduced the pharmacogenetics widget in the Open Targets Platform, which brings in data from PharmGKB on the influence of genetic variation on drug responses. Different predicted functional consequences of pharmacogenetics variants from the PharmGKB data. What's new?

Pharmacogenetics

Pharmacogenetics Drugs Therapies Disease

Dysregulation of Human Hepatic Drug Transporters by Proinflammatory Cytokines [Metabolism, Transport, and Pharmacogenetics]

ASPET

AUGUST 5, 2024

Proinflammatory cytokines, elevated during inflammation caused by infection and/or autoimmune disorders, result in reduced clearance of drugs eliminated primarily by cytochrome P450 enzymes (CYPs). However, the effect of cytokines on hepatic drug transporter expression or activity has not been well-studied. or 1 ng/mL).

Pharmacogenetics

Pharmacogenetics Pharmacokinetics Drugs

Gene polymorphisms and drug-drug interactions determine the metabolic profile of blonanserin [Metabolism, Transport, and Pharmacogenetics]

ASPET

OCTOBER 20, 2023

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Clearance of blonanserin by CYP3A4.4,

Pharmacogenetics

Pharmacogenetics Drugs

Open Targets Platform 24.03 has been released!

The Open Targets Blog

MARCH 20, 2024

The team identified 370 priority drug targets for 27 cancer types in a truly data-driven approach, leveraging clinical-relevant transcriptional signatures, metabolic and proteomics data, protein-protein interaction networks and more. In addition, we now indicate whether a target is a direct target of the drug. DOI: 10.1016/j.ccell.2023.12.016

Pharmacogenetics

Pharmacogenetics Disease Drugs Research

Central Nervous System Distributional Kinetics of Selected Histone Deacetylase Inhibitors [Metabolism, Transport, and Pharmacogenetics]

ASPET

APRIL 26, 2024

This lack of activity could be due to insufficient CNS exposure to the unbound drug. Although many HDACIs have shown potential in in vitro studies, they have had modest efficacy in vivo. Both compounds undergo in vitro degradation in mouse plasma, requiring precautions during sample processing.

Pharmacogenetics

Pharmacogenetics Pharmacokinetics Clinical Trials Trials

Pharmacokinetics of panobinostat: Inter-species difference in metabolic stability [Metabolism, Transport, and Pharmacogenetics]

ASPET

FEBRUARY 26, 2024

This lack of translation between in vitro metabolism assays and in vivo disposition can confound drug development. This suggests that the inter-strain difference in enzymatic activity did not affect the in vivo pharmacokinetic behavior of panobinostat and its CNS distribution in mice.

Metabolic Stability

Metabolic Stability Pharmacokinetics Pharmacogenetics Treatment

Characterization of hOAT4 and mOat5 as functional orthologs for renal anion uptake and efflux transport [Metabolism, Transport, and Pharmacogenetics]

ASPET

APRIL 16, 2024

Organic anions (OA) are compounds including drugs or toxicants that are negatively charged at physiological pH and are typically transported by Organic Anion Transporters (OATs). For the profile of OTA inhibition by OAs, IC 50 values were determined for several clinically important drugs and toxicants. pmol/cm 2 , respectively.

Pharmacogenetics

Pharmacogenetics Drugs

Lenacapavir Exhibits Atropisomerism - Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway [Metabolism, Transport, and Pharmacogenetics]

ASPET

AUGUST 8, 2024

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few FDA-approved drugs that exhibit atropisomerism. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole body autoradiography in rats.

Pharmacogenetics

Pharmacogenetics Pharmacokinetics FDA Approval Virus

Humanization of SLCO2B1 in rats increases rCYP3A1 protein expression but not the metabolism of erlotinib to OSI-420 [Metabolism, Transport, and Pharmacogenetics]

ASPET

MARCH 6, 2024

A first pharmacological phenotyping with the OATP2B1 substrate-drug atorvastatin revealed reduced hepatic content and increased expression of rCYP3A1 in the humanized animals. In order to assess the in vivo relevance of the transporter, we applied SLCO2B1 +/+ knock-in and Slco2b1 -/- knock-out rats.

Protein Expression

Protein Expression Pharmacogenetics Treatment Drugs

Factors influencing the Central Nervous System (CNS) distribution of the ATR inhibitor elimusertib (BAY1895344): Implications for the treatment of CNS tumors [Metabolism, Transport, and Pharmacogenetics]

ASPET

SEPTEMBER 16, 2024

GBM has a poor prognosis despite aggressive treatment, in part due to lack of adequate drug permeability at the BBB. CNS distribution of elimusertib is partially limited by P-gp efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain.

Pharmacogenetics

Pharmacogenetics DNA Pharmacokinetics Treatment

A Pilot Study to Assess the Suitability of Riboflavin as A Surrogate Marker of Breast Cancer Resistance Protein (BCRP) in Healthy Participants [Metabolism, Transport, and Pharmacogenetics]

ASPET

JANUARY 31, 2024

First, we assessed the substrate potential of riboflavin towards other major drug transporters using established transfected cell systems. Overall, these data indicate that plasma riboflavin is a promising biomarker of BCRP that may offer a possibility to assess drug candidate as a BCRP modulator in early drug development.

Pharmacogenetics

Pharmacogenetics Pharmacokinetics Drug Development Drugs

Open Targets Platform 23.12 has been released!

The Open Targets Blog

NOVEMBER 30, 2023

Target prioritisation A major new feature of this release is the Target Prioritisation view, which provides an assessment of target-specific properties of interest when evaluating the suitability of a target for a drug discovery programme. It is presented here with an additional layer of analysis with a drug discovery focus.

Pharmacogenetics

Pharmacogenetics Small Molecule Disease Drugs

Preclinical systemic pharmacokinetics, dose-proportionality, and CNS distribution of the ATM inhibitor WSD0628, a novel radiosensitizer for the treatment of brain tumors [Metabolism, Transport, and Pharmacogenetics]

ASPET

JUNE 10, 2024

Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier (BBB). Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors.

Pharmacokinetics

Pharmacokinetics Pharmacogenetics Treatment DNA

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations [Metabolism, Transport, and Pharmacogenetics]

ASPET

AUGUST 4, 2023

Results highlight the potential interplay between time-dependent and reversible inhibition of intestinal CYP3A as the mechanism underlying natural product-drug interactions, even after acute exposure to the precipitant.

Pharmacokinetics

Pharmacokinetics Pharmacogenetics Production Drugs

Significance of organic anion transporter 2 and organic cation transporter 2 in creatinine clearance: Mechanistic evaluation using freshly-prepared human primary renal proximal tubule cells [Metabolism, Transport, and Pharmacogenetics]

ASPET

NOVEMBER 17, 2023

Quantitative pharmacokinetic models should therefore focus on OCT2/MATE when describing serum creatinine and creatinine clearance modulation by inhibitor drugs and genotype- or disease-related activity changes.

Pharmacogenetics

Pharmacogenetics Pharmacokinetics Disease Drugs

Agena Bioscience Granted EUA for High-Throughput, Low-Cost SARS-CoV-2 Panel

The Pharma Data

OCTOBER 27, 2020

Food and Drug Administration (FDA). SAN DIEGO , Oct. Clinical laboratories can process thousands of samples each day for less than $10 per sample running the assay on a single MassARRAY instrument, making it one of the highest throughput SARS-CoV-2 tests available under the Emergency Use Authorization program. SOURCE Agena Bioscience.

Pharmacogenetics

Pharmacogenetics Laboratories Clinical Research FDA

Drug Discovery Digest

Integrating pharmacogenetics data: a new lens for target prioritisation

Dysregulation of Human Hepatic Drug Transporters by Proinflammatory Cytokines [Metabolism, Transport, and Pharmacogenetics]

Trending Sources

Gene polymorphisms and drug-drug interactions determine the metabolic profile of blonanserin [Metabolism, Transport, and Pharmacogenetics]

Open Targets Platform 24.03 has been released!

Central Nervous System Distributional Kinetics of Selected Histone Deacetylase Inhibitors [Metabolism, Transport, and Pharmacogenetics]

Pharmacokinetics of panobinostat: Inter-species difference in metabolic stability [Metabolism, Transport, and Pharmacogenetics]

Characterization of hOAT4 and mOat5 as functional orthologs for renal anion uptake and efflux transport [Metabolism, Transport, and Pharmacogenetics]

Lenacapavir Exhibits Atropisomerism - Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway [Metabolism, Transport, and Pharmacogenetics]

Humanization of SLCO2B1 in rats increases rCYP3A1 protein expression but not the metabolism of erlotinib to OSI-420 [Metabolism, Transport, and Pharmacogenetics]

Factors influencing the Central Nervous System (CNS) distribution of the ATR inhibitor elimusertib (BAY1895344): Implications for the treatment of CNS tumors [Metabolism, Transport, and Pharmacogenetics]

A Pilot Study to Assess the Suitability of Riboflavin as A Surrogate Marker of Breast Cancer Resistance Protein (BCRP) in Healthy Participants [Metabolism, Transport, and Pharmacogenetics]

Open Targets Platform 23.12 has been released!

Preclinical systemic pharmacokinetics, dose-proportionality, and CNS distribution of the ATM inhibitor WSD0628, a novel radiosensitizer for the treatment of brain tumors [Metabolism, Transport, and Pharmacogenetics]

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations [Metabolism, Transport, and Pharmacogenetics]

Significance of organic anion transporter 2 and organic cation transporter 2 in creatinine clearance: Mechanistic evaluation using freshly-prepared human primary renal proximal tubule cells [Metabolism, Transport, and Pharmacogenetics]

Agena Bioscience Granted EUA for High-Throughput, Low-Cost SARS-CoV-2 Panel

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