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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

Photosafety testing of dermally-applied chemicals based on photochemical and cassette-dosing pharmacokinetic data

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Asian Journal of Pharmaceutical Sciences 2016年第1期11卷 237-238页

作者： Hiroto Ohtake Yukiko Suzuki Masashi Kato Yoshiki Seto Satomi Onoue department of pharmacokinetics and Pharmacodynamics School of Pharmaceutical Sciences University of Shizuoka

Drug-induced phototoxicity is elicited by exposure of skin and/or eyes to topical or systemic administration of chemicals,followed by exposure to *** photosafety testing,a new screening strategy,employing in vitro photochemical/photobiological and in vivo cassette-dosing pharmacokinetic(PK)studies,was proposed[1,2].The screening system provided reliable phototoxic predictions of tested chemicals at least within the same chemical series;however,the applicability of the proposed strategy is not fully understood.

关键词： Photosafety assessment Phototoxicity Photoreactivity pharmacokinetics

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

Liquid chromatography-tandem mass spectrometry method for the estimation of adefovir in human plasma:Application to a pharmacokinetic study

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Journal of Pharmaceutical Analysis 2015年第3期5卷 190-199页

作者： Dipanjan Goswami Sanjay Gurule Arabinda Saha Poonam Vats Arshad Khuroo Tausif Monif Sun Pharmaceutical industries Ltd. department of Clinical Pharmacology and pharmacokinetics Ranbaxy LaboratoriesLtd.

An analytical method based on solid phase extraction was developed and validated for analysis of adefovir in human plasma. Adefovir-d4 was used as an internal standard and Synergi MAX RP80A （150rnmx4.6mm. 41am） column provided the desired chromatographic separation of compounds followed by detection with mass spectrometry. The method used simple isocratic chromato- graphic condition and mass spectrometric detection in the positive ionization mode. The calibration cuives were linear over the range of 0.50-42.47 ng/mL with the lower limit of quantitation validated at 0.50 ng/mL. Matrix effect was assessed by post-column infusion experiment to monitor phospholipids and post- extraction addition experiment was performed. The degree of matrix effect for adefovir was determined as 7.5% and ion-enhancement in five different lots of human plasma was 7.1% and had no impact on study samples analysis with 4.5 rain run time. The intra- and inter-day precision values were within 7.7% and 7.8%, respectively, for adefovir at the lower limit of quantification level. Validated bioanalytical method was successfully applied to clinical sample analysis.

关键词： Liquid chromatography-tandem massspectrometry Solid phase extraction Pharmacokinetic study

Evaluation of the metabolism of PEP06,an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells

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Journal of Pharmaceutical Analysis 2022年第5期12卷 766-773页

作者： Liyun Niu Huiyu Zhou Yueru Lian Ya Gao Yulu Liu Ruolan Gu Zhuona Wu Xiaoxia Zhu Hui Gan Zhiyun Meng Guifang Dou State Key Laboratory of Drug Metabolism and pharmacokinetics Department of Pharmaceutical SciencesBeijing Institute of Radiation MedicineBeijing100850China Henan University KaifengHenan475004China

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp(RGDRGD)30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N *** active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral ***,little is known about the kinetics and degradation products of PEP06 in vitro or in *** this study,we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species;we further identified the degradation characteristics of its cleavage ***06 underwent rapid enzymatic degradation in multiple types of living cells,and the liver,kidney,and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of *** identified metabolites of PEP06 using full-scan mass spectrometry(MS)and tandem MS(MS2),wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide,formed by successive losses of amino *** metabolites were C and N terminal truncated products of *** structures of 11 metabolites(M6,M7,M16,M17,M21,M25,M33,M34,M39,M40,and M42)were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized *** have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06,which can support further drug research.

关键词： PEP06 HRMS Metabolic stability Metabolites identification

Simultaneous quantitation of atorvastatin and its two active metabolites in human plasma by liquid chromatography/(–) electrospray tandem mass spectrometry

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Journal of Pharmaceutical Analysis 2014年第1期4卷 26-36页

作者： Pankaj Partani S.Manaswita Verma Sanjay Gurule Arshad Khuroo Tausif Monif department of Clinical Pharmacology and pharmacokinetics Ranbaxy Research Laboratories Plot: GP-5 Sec-18 HSIIDC department of Pharmaceutical Sciences Birla Institute of Technology

A sensitive, accurate and selective liquid chromatography-tandem mass spectrometry method （LC-MS/MS） was developed and validated for the simultaneous quantitation of atorvastatin （AT） and its equipotent hydroxyl metabolites, 2-hydroxy atorvastatin （2-AT） and 4-hydroxy atorvastatin （4-AT）, in human plasma. Electrospray ionization （ESI） interface in negative ion mode was selected to improve the selectivity and the sensitivity required for this application. Additionally, a solid phase extraction （SPE） step was performed to reduce any ion-suppression and/or enhancement effects. The separation of all compounds was achieved in less than 6 min using a C18 reverse-phase fused-cores column and a mobile phase, composed of a mixture of 0.005%formic acid in water：acetonitrile：methanol （35：25：40, v/v/v）, in isocratic mode at a flow rate of 0.6 mL/min. The method has lower limit of quantitation （LLOQ） of 0.050 ng/mL for all analytes. The method has shown tremendous reproducibility, with intra-and inter-day precision less than 6.6%, and intra- and inter-day accuracy within 74.3% of nominal values, for all analytes, and has proved to be highly reliable for the analysis of clinical samples.

关键词： Atorvastatin LC-MS/MS Solid phase extractionpharmacokinetics Method validation

Liquid chromatography tandem mass spectrometry method for the estimation of lamotrigine in human plasma:Application to a pharmacokinetic study

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Journal of Pharmaceutical Analysis 2013年第2期3卷 75-83页

作者： Santosh Ghatol Vatsal Vithlani Sanjay Gurule Arshad Khuroo Tausif Monif Pankaj Partani department of Clinical Pharmacology and pharmacokinetics Ranbaxy Research LaboratoriesPlot:GP-VSec-18HSIIDCGurgaon 122015HaryanaIndia

A reliable,selective and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of lamotrigine in human plasma using lamotrigine13C3,d3 as an internal *** and internal standard were extracted from human plasma by solid-phase extraction and detected in positive ion mode by tandem mass spectrometry with electrospray ionization（ESI） *** separation was performed on a Chromolith s SpeedROD;RP-18e column（50-4.6 mm i.d.） using acetonitrile：570.1 mM ammonium formate solution（90：10,v/v） as the mobile phase at a flow rate of 0.500 mL/*** calibration curves were linear over the range of 5.02-1226.47 ng/mL with the lower limit of quantitation validated at 5.02 ng/*** analytes were found stable in human plasma through three freeze（-20℃）-thaw（ice-cold water bath） cycles and under storage on bench-top in ice-cold water bath for at least 6.8 h,and also in the mobile phase at 10℃ for at least *** method has shown good reproducibility,as the intra-and inter-day precisions were within 3.0%,while the accuracies were within 76.0% of nominal *** validated LC-MS/MS method was applied for the evaluation of pharmacokinetic and bioequivalence parameters of lamotrigine after an oral administration of 50mg lamotrigine tablet to thirty-two healthy adult male volunteers.

关键词： Lamotrigine Liquid chromatography/tandem mass spectrometry Solid phase extraction Pharmacokinetic study

Synthesis and activity evaluation of some novel derivatives of 4,5,6,7-tetrahydrothieno [3,2-c]-pyridine

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Chinese Chemical Letters 2008年第6期19卷 689-692页

作者： Die Cheng Deng Ke Liu MO Liu Ying Liu Wei Ren Xu Chang Xiao Liu department of Pharmaceutical Engineering School of Chemical Engineering and Technology Tianjin University Tianjin 300072 China State Key Laboratory of pharmacokinetics and Pharmacodynamics Tianjin Institute of Pharmaceutical Research Tianjin 300193 China

Two series of novel derivatives of4,5,6,7-tetrahydrothieno [3,2-c]pyridine were synthesized and structurally characterized by 1^H NMR and MS. Their in vivo antiplatelet aggregation activities were evaluated.

关键词： Thienopyridines Antiplatelet aggregation activities P2Y12 receptors

Target-responsive subcellular catabolism analysis for early-stage antibody-drug conjugates screening and assessment

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Acta Pharmaceutica Sinica B 2021年第12期11卷 4020-4031页

作者： Hua Sang Jiali Liu Fang Zhou Xiaofang Zhang Jingwei Zhang Yazhong Liu Guangji Wang Hui Ye Jiangsu Provincial Key Laboratory of Drug Metabolism and pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China department of Pharmacy the Affiliated Hospital of Nantong UniversityNantong 226001China

Events including antibody-antigen affinity,internalization,trafficking and lysosomal proteolysis combinatorially determine the efficiency of antibody-drug conjugate(ADC) catabolism and hence the ***,an approach that conveniently identifies proteins requisite for payload release and the ensuing toxicity for mechanistic studies and quality assessment is *** the plethora of ADC candidates under development,we developed a target-responsive subcellular catabolism(TARSC) approach that examines ADC catabolism and probes changes in response to targeted interferences of proteins of *** firstly applied TARSC to study the commercial T-DM1 and the *** recorded unequivocal catabolic behaviors regardless of the absence and presence of the targeted *** negligible differences in TARSC profiles agreed with their undifferentiated anti-tumoral efficacy according to further in vitro viability and in vivo tumor growth assays,highlighting TARSC analysis as a useful tool for biosimilarity assessment and functional dissection of proteins requisite for ADC ***,we employed TARSC to investigate the catabolic behavior of a new trastuzumab-toxin ***,TARSC can not only characterize ADC catabolism at(sub)cellular level but also comprehensively determine which protein targets affect payload release and therapeutic *** use of TARSC is thus anticipated in early-stage screening,quality assessment and mechanistic investigations of ADCs.

关键词： ADC Target-responsive subcellular catabolism(TARSC) T-DM1 Therapeutic efficacy Screening Biosimilarity