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pharmacokinetics of monoclonal antibodies ]nd Fc-fusion proteins

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Protein & Cell 2018年第1期9卷 15-32页

作者： Liming Liu department of pharmacokinetics Pharrnacodynamics and Drug Metabolism MRL West Point PA 19486 USA

There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or *** protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer ***. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and *** binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.

关键词： monoclonal antibody (mAb) Fc-fusionprotein pharmacokineUcs FcRn target-mediated drugdisposition (TMDD) glycosylation anti-drug antibody (ADA)human PK prediction

drug metabolism in drug discovery and development

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Acta Pharmaceutica Sinica B 2018年第5期8卷 721-732页

作者： Zhoupeng Zhang Wei Tang department of pharmacokinetics Pharmacodynamics and Drug Metabolism Merck Sharp & Dohme Corp. Shanghai ChemPartners

drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics(PK), pharmacodynamics(PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure–activity relationships(SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism,drug–drug interactions(DDI) and formation of reactive metabolites.

关键词： Bioactivation drug discovery and development drug metabolism Metabolite pharmacokinetics Pharmacodynamics Safety Toxicity

Characteristics of β-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats

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Acta Pharmacologica Sinica 2019年第8期40卷 1106-1118页

作者： Kai-jing Zhao Yang Chen Shi-jin Hong Yi-ting Yang Jiong Xu Han-yu Yang Liang Zhu Ming Liu Qiu-shi Xie Xian-ge Tang Ting-ting Yang Ya-qian Zhou Li Liu Xiao-dong Liu Center of drug metabolism and pharmacokinetics School of PharmacyChina Pharmaceutical University

Cinnamic acid and its analogues(pyragrel and ozagrel)undergo chain-shortened(β-oxidative)and reductive metabolism on acyl side *** this study,we characterized the β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes,hepatic mitochondrial,and microsomal systems.A compartmental model including parent compounds and metabolites was developed to characterize in vivo β-oxidative and reductive metabolism following an intravenous dose of parent compounds to *** fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred *** showed that hepatic microsomal CYP450s did not catalyze β-oxidative or reductive metabolism of the three *** to β-oxidation of fatty acids,β-oxidative metabolism on their acyl side chain occurred mainly in mitochondria,which was highly dependent on ATP,CoA and NAD~+.Fatty acids and NADH inhibited the β-oxidative *** metabolism occurred in both mitochondria and *** in mitochondria was ATP-,CoA-,and NAD(P)H-dependent and reversible,which was suppressed by enoyl reductase inhibitor *** in microsomes was ATP-,CoA-,and NADPH-dependent but little affected by *** plasma concentrations of β-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental *** estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles,implicating significance of in vitro *** findings demonstrate the roles of hepatic mitochondria and microsomes in β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.

关键词： antiplatelet drug cinnamic acid pyragrel ozagrel drug metabolism hepatocytes mitochondria microsomes pharmacokinetics in vitro-in vivo correlation

Breaking new ground in photocatalysis:lutetium texaphyrin as a trigger for pyroptosis through biomolecular photoredox reactions

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Science China Chemistry 2025年第1期68卷 1-2页

作者： Qihang Ding Mengrong He Meijia Gu department of Chemistry Korea UniversitySeoul 02841Republic of Korea department of Ultrasound Medicine Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Key Laboratory of Combinatorial Biosynthesis and drug Discovery(MOE) School of Pharmaceutical SciencesWuhan UniversityWuhan 430071China

Malignant neoplasms consistently pose a significant threat to global public health^([1,2]).In recent years,immunotherapy has demonstrated remarkable clinical success;however,its efficacy is limited by the scarcity of immune cell infiltration within tumor *** pyroptosis,a gasdermin-mediated process characterized by cellular swelling,rupture,and the release of intracellular contents such as IL-1β,IL-18,ATP,HMGB1,plays a crucial role in this context^([3,4]).

关键词： neoplasms clinical rupture

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

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2751-2777页

作者： Yurong Lai Xiaoyan Chu Li Di Wei Gao Yingying Guo Xingrong Liu Chuang Lu Jialin Mao Hong Shen Huaping Tang Cindy Q.Xia Lei Zhang Xinxin Ding drug metabolism Gilead Sciences Inc.Foster CityCA 94404USA department of pharmacokinetics Pharmacodynamics and Drug MetabolismMerck&Co.Inc.KenilworthNJ 07033USA pharmacokinetics Dynamics and MetabolismPﬁzer Worldwide Research and DevelopmentGrotonCT 06340USA Eli Lilly and Company IndianapolisIN 46221USA drug metabolism and pharmacokinetics BiogenCambridgeMA 02142USA drug metabolism and pharmacokinetics Accent TherapeuticsInc.LexingtonMA 02421USA department of drug metabolism and pharmacokinetics GenentechA Member of the Roche GroupSouth San FranciscoCA 94080USA drug metabolism and pharmacokinetics department Bristol-Myers Squibb CompanyPrincetonNJ 08540USA Bioanalysis and Biomarkers Glaxo Smith KlineKing of the PrussiaPA 19406USA department of drug metabolism and pharmacokinetics Takeda Pharmaceuticals International Co.CambridgeMA 02139USA Ofﬁce of Research and Standards Ofﬁce of Generic DrugsCDERFDASilver SpringMD 20993USA department of Pharmacology and Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85721USA Current afﬁliation:Translational Medicine EMD Serono Research&Development InstituteInc.BillericaMA 01821USA Current afﬁliation:drug metabolism Gilead Sciences Inc.Foster CityCA 94404USA

drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical *** 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 *** 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 *** importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly *** 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 *** 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.

关键词： drug discovery and development New drug application Biologics license application pharmacokinetics ADME New modalities Model-informed drug development Micro-physiological systems

Chiral phosphoramidite ligand-modulated palladium auto-tandem catalysis for asymmetric dehydrogenative dienylation of imines with α-alkenes

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Science China Chemistry 2025年

作者： Zhong-Sheng Nong Hao-Fan Qian Ying-Chun Chen Pu-Sheng Wang Liu-Zhu Gong Hefei National Research Center for Physical Sciences at the Microscale and department of Chemistry University of Science and Technology of China Key Laboratory of drug Targeting and drug Delivery System (Sichuan University) Ministry of Education and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University School of Materials and Chemistry Southwest University of Science and Technology

The development of efficient processes allowing rapid access to complex chiral molecules from easily available alkenes is a long-term pursuit in the synthetic chemistry community. Transition metal-catalyzed asymmetric functionalization of allylic C–H bond represents a unique alternative toward this goal. However, enantioselective dehydrogenative transformation of olefins to value-added optically enriched molecules remains yet to be discovered. Here, we report a highly enantioselective dehydrogenative dienylation of imines with unactivated α-alkenes driven by the synergistic action of palladium complex and carboxylic acid. Chiral phosphoramidite ligands turned out to be superior in modulating the performance of palladium autotandem catalysis and allowed a broad range of α-alkenes and imines to be transformed into chiral dienylamines. Mechanistic studies suggest that the dienes could be in situ generated from α-alkenes through a palladium(0)-mediated dehydrogenative process in the presence of excess benzoquinone oxidants, and then participated in the Pd-chiral phosphoramidite-catalyzed intermolecular vinylogous-type addition to the imines activated by the carboxylic acid co-catalyst. Notably, the second β-H elimination occurring in the dienylation event might be the turnover-limiting step.

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Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

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Neural Regeneration Research 2025年第5期20卷 1258-1276页

作者： Qing Qiu Mengting Yang Danfeng Gong Haiying Liang Tingting Chen department of Pharmacology School of PharmacyNantong UniversityNantongJiangsu ProvinceChina Jiangsu Province Key Laboratory of Inflammation and Molecular drug Target NantongJiangsu ProvinceChina department of Pharmacy Longyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujian ProvinceChina

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be u

关键词： astrocytes calcium channels central nervous system extracellular ion concentration microglia neurological disorders neurons potassium channels

Rifabutin reduces systemic exposure of an antimalarial drug 97/78 upon co-administration in rats:an in-vivo & in-vitro analysis

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Asian Pacific Journal of Tropical Medicine 2015年第8期8卷 620-625页

作者： Yeshwant Singh Mahendra Kumar Hidau Shio Kumar Singh pharmacokinetics & metabolism Division CSIR-Central Drug Research Institute Academy of Scientific and Innovative Research

Objective: To determine the potential drug-drug interactions between anti-malarial candidate 97/78 and anti-tubercular drug rifabutin in-vivo in rats followed by in-vitro investigation of the underlying mechanisms of drug interaction. Methods: Single oral dose study was conducted in male and female rats at 40 mg/kg and 70 mg/kg for 97/78 and rifabutin respectively. Results: It was reported that rifabutin co-administration altered pharmacokinetics of 97/63(active metabolite of 97/78). A significant decrease was reported in the systemic exposure of 97/63 by a factor of 3-4. The AUC0-last values were(4.03 ± 0.60) and(5.44 ± 1.15) μg·h·m L-1 upon 97/78 administration alone, while the values were decreased to(1.13 ± 0.10) and(1.23 ± 1.13) μg·h·m L-1 upon rifabutin co-administration in male and female rats respectively. Statistically significant differences were also reported in Cmax and Tmax values upon rifabutin co-administration. In-vitro drug metabolism study in rat liver microsomes has shown that the metabolism of 97/63 was increased by 10%-12% upon rifabutin co-incubation. The extent of plasma protein binding of 97/63 was found to be decreased from 54%-55% to 6%-8% upon rifabutin addition. Conclusions: It was concluded that rifabutin co-administration altered PK parameters of 97/63 in SD rats. However, no intersex influences were reported in the interaction pattern. The results obtained in the in-vivo study were well correlated with the invitro findings and can further be applied to explore other aspects of potential drug interactions between these two drugs.

关键词： Accumulation Relative bioavailability Sex effect pharmacokinetics

Quantitative determination of D_(4)-cystine in mice using LC-MS/MS and its application to the assessment of pharmacokinetics and bioavailability

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Journal of Pharmaceutical Analysis 2021年第5期11卷 580-587页

作者： Shuning Li Zhenyao Lu Li Jiao Ran Zhang Yu Hong Jiye Aa Guangji Wang Jiangsu Province Key Laboratory of drug metabolism and pharmacokinetics China Pharmaceutical UniversityNanjingJiangsu210009China

Cystine is the primary source material for the synthesis of ***,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate calibration curves for the determination of levels of D_(4)-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Validation assessments proved the sensitivity,specificity and reproducibility of the method with a lower limit of quantification(LLOQ)of 5 ng/mL over 5e5000 ng/mL in *** pharmacokinetics of D_(4)-cystine were evaluated after administering injections and oral solutions,both of which minimally impacted endogenous cystine *** absolute bioavailability of cystine was 18.6%,15.1%and 25.6%at doses of 25,50 and 100 mg/kg,*** injected D_(4)-cystine resulted in dramatically high plasma levels with reduced levels in the brain and *** administered D_(4)-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung,kidney,heart and brain.

关键词： Cystine LC-MS/MS pharmacokinetics Distribution Absolute bioavailability