Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Can formulation and drug delivery reduce attrition during drug discovery and development--review of feasibility,benefits and challenges

Drug discovery and development has become longer and costlier process.The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards“me too”drugs and improved generics(505(b)(2))fillings.The discontinuance of molecules at late stage clinical trials is common these years.The molecules are withdrawn at various stages of discovery and development process for reasons such as poor ADME properties,lack of efficacy and safety reasons.Hence this review focuses on possible applications of formulation and drug delivery to salvage molecules and improve the drugability.The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail.

MKK4 inhibitor:the hope for liver failure prevention and potential small liver graft transplantation

Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.

HIF-1α pathway: role, regulation and intervention for cancer therapy

Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.