Drug metabolism and bioanalysis letters最新文献

{"title":"A Simplified Method for Determining Blood-to-Plasma Ratios <i>in vitro</i> and <i>ex vivo</i> by Matrix Matching with Blank Blood or Plasma.","authors":"Xiaomei Zhang, Gary J Jenkins, Kelly E Desino, Jinrong Liu, Mary Larsen, David M Stresser","doi":"10.2174/2949681016666230817150551","DOIUrl":"10.2174/2949681016666230817150551","url":null,"abstract":"<p><strong>Objective: </strong>This work describes a simplified, 96-well plate method for determining the blood-to-plasma concentration ratio (BP ratio) for small molecules.</p><p><strong>Methods: </strong>The need for calibration curves was eliminated using a matrix-matching approach in which blood samples were mixed with blank plasma and plasma samples were mixed with blank blood. As a result, both blood- and plasma-origin samples shared an equivalent matrix ahead of bioanalysis. In the <i>in vitro</i> assay, identical sample matrices were achieved by using the same source of blank plasma and blood.</p><p><strong>Results: </strong>In humans, a good correlation (R2 = 0.84) was observed between the data obtained in this matrix-matching method and literature values for 11 commercial compounds possessing a wide range of logD values across multiple chemical classes. In addition, this method showed good agreement with <i>in vitro</i> BP ratios for 10 proprietary compounds determined radiometrically (R2 = 0.72) in human and preclinical species. Finally, the <i>in vitro</i> matrix matching method compared favorably to BP ratios determined <i>ex vivo</i> for 13 proprietary and literature compounds (R2 = 0.87) in rat.</p><p><strong>Conclusion: </strong>This method, suitable for <i>in vitro</i> and <i>ex vivo</i> BP ratio determinations, is operationally efficient, robust, and a useful improvement upon previously published methods.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":"113-120"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10078110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP2D6 and CYP2C19 Genes Associated with Tricontinental and Latin American Ancestry of Pe-ruvians.","authors":"Angel T Alvarado, María Saravia, Ricardo Losno, Ricardo Pariona, Ana María Muñoz, Roberto O Ybañez-Julca, Berta Loja, María R Bendezú, Jorge A García, Felipe Surco-Laos, Doris Laos-Anchante, Haydee Chávez, Priscilia Aguilar, Mario Pineda","doi":"10.2174/1872312815666221213151140","DOIUrl":"10.2174/1872312815666221213151140","url":null,"abstract":"<p><p>Precision medicine seeks to individualize the dose from the beginning of phar-macological therapy based on the characteristics of each patient, genes involved in the metabolic phenotype, ethnicity or miscegenation, with the purpose to minimize adverse effects and optimize drug efficacy. The objective was to re-view studies that describe the association of the CYP2D6 and CYP2C19 genes with the tricontinental and Latin American ancestry of Peruvians. A biblio-graphic search was carried out in PubMed/Medline and SciELO, with various descriptors in Spanish and English. The results of this review confirm that the ethnic origin of Peruvians is triconti-nental due to European (mainly Spanish), African and Asian migration, in addi-tion to Latin American migration, being 60.2% mixed, 25.8% Amerindian, 5.9% white, 3.6% African descent, 1.2% Chinese and Japanese descent, and 3.3% unspecified. Studies on CYP2C19*3, CYP2D6*2, *3 and *6 have been reported in Peruvians, and the frequency is similar to that studied in Ecuadori-ans and Colombians. The CYP2C19*3, CYP2D6*3, and CYP2D6*6 alleles found in Peruvians are common in Europeans, Africans, and Asians; while CYP2D6*4 in Africans and CYP2D6*2 related to Asians. In some studies, the ethnic/gene association has not been demonstrated; while others have shown a significant association, which is why further investigation is warranted. It is concluded that the studies on CYP2D6 and CYP2C19 genes associated with the tricontinental and Latin American ancestry of Peruvians are little, and ac-cording to what has been investigated, the CYP2C19*3, CYP2D6*2, *3, *4 and *6 alleles have more related to their ancestry.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10043248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism-based inhibition of CYP3A subfamilies by macrolide antibiotics and piperine.","authors":"Toshiro Niwa, Risa Ishii","doi":"10.2174/2949681015666220804103005","DOIUrl":"10.2174/2949681015666220804103005","url":null,"abstract":"<p><strong>Objective: </strong>The mechanism-based inhibition of macrolide antibiotics, such as erythromycin and clarithromycin, and piperine on testosterone 6β-hydroxylation activities by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared.</p><p><strong>Methods: </strong>6β-Hydroxy testosterone was determined by high-performance liquid chromatography.</p><p><strong>Results: </strong>Although preincubation with erythromycin and clarithromycin decreased CYP3A4-meditaed testosterone 6β- hydroxylation in a time-dependent manner, and the estimated maximum inactivation rate constant (k inact ) and the inactivation rate constant reaching half of k inact (K i ) for erythromycin were approximately 1/2 and 1/5, respectively, of those for clarithromycin. Obvious preincubation time-dependent inhibition of erythromycin against CYP3A5 and CYP3A7 was not observed. Piperine exhibited preincubation time- dependent inhibition, and the calculated K i and k inact values for CYP3A4 were approximately 1/7 and 1/2, respectively, of those for CYP3A5.</p><p><strong>Conclusion: </strong>It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40333407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of nano lipid carrier loaded transdermal patch of rizatriptan benzoate.","authors":"Sayani Bhattacharyya, Lavanya Nanjareddy","doi":"10.2174/2949681015666220609095706","DOIUrl":"10.2174/2949681015666220609095706","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a neurological disorder and is accompanied by different painful episodes. Hence the maintenance of a steady-state concentration of drug can be beneficial for the patients suffering with migraine. The present investigation focuses on the development of nano lipid carriers (NLCs) loaded transdermal patch of rizatriptan benzoate to sustain the effect of the drug for the enhancement of therapeutic effects.</p><p><strong>Method: </strong>Stearic acid and peanut oil were used to make the NLCs. A central composite design was employed to observe the effect of formulation factors like solid lipid ratio, phase volume ratio, and concentration of surfactants on the formation of nanoparticles. The effects were evaluated for the responses like particle size and entrapment of the drug in the nanocarriers. The optimized formulation was subjected to compatibility, thermal, surface characteristics, and surface morphology studies. The optimized formulation was dispersed in HPMC 15CPS and PVP K30 polymer matrix and the transdermal patch was evaluated for its mechanical properties, drug release study, and skin irritation study.</p><p><strong>Results: </strong>The experimental design was suitable to produce nanosized stable lipid carriers of the drug with high drug entrapment. The drug and excipients were found to be compatible. The thermal and surface characteristics study proved the high loading of drug in the nanoparticles. The surface morphology study showed the formation of irregular-shaped NLCs. The transdermal patch had good mechanical properties. The ex vivo study of the formulated patch showed a sustained release of the drug over 24h. No skin irritation was reported from the transdermal patch.</p><p><strong>Conclusion: </strong>Therefore, it can be concluded that the nanoparticles loaded transdermal patch of rizatriptan benzoate can be promising in controlling the divergent phases of migraine.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40576330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medicinal Importance, Pharmacological Activities and Analytical Aspects of a Flavonoid Glycoside 'Nicotiflorin' in the Medicine.","authors":"Dinesh Kumar Patel","doi":"10.2174/1872312815666220404110200","DOIUrl":"https://doi.org/10.2174/1872312815666220404110200","url":null,"abstract":"<p><strong>Background: </strong>Herbal products are derived from different natural sources, mainly used as a source of food material and medicine in the health sectors since ancient times. Herbal products have gained popularity in modern medicine due to their beneficial health properties and pharmacological activities. Flavonoids are an important class of secondary metabolites found to be present in medicinal plants and their derived products. Flavonoids have been known for their anti-allergic, anti-bacterial, anti-diabetic, anti-inflammatory, anti-viral, anti-proliferative, anti-mutagenic, antithrombotic, anti-carcinogenic, anti-oxidant and hepatoprotective activities in the medicine. Nicotiflorin is a flavonoidal class phytochemical, found in medicinal plants, including Traditional Chinese medicine.</p><p><strong>Methods: </strong>Scientific data on the medicinal importance and pharmacological activities of nicotiflorin have been collected and analyzed in the present work in order to know the therapeutic importance of nicotiflorin in medicine. Scientific data have been collected from Google, Google Scholar, Science Direct, PubMed and Scopus and analyzed in the present work. Analytical techniques data of separation, isolation and identification of nicotiflorin have also been collected and presented in the current work. Further biological importance of flavonoidal class phytochemicals was also discussed in the present work to understand the biological importance of nicotiflorin in medicine as it belongs to the flavonoid class.</p><p><strong>Results: </strong>Scientific data analysis revealed the therapeutic importance and pharmacological activities of nicotiflorin. Nicotiflorin has significant biological potential against coronavirus, ischemia, renal impairment, hepatic complication, memory dysfunction and myocardial infarction. The biological potential of nicotiflorin against α-glucosidase and α-amylase enzymes, multiple myeloma cells and insulin secretion has also been discussed in the present work. Analytical data revealed the significance of modern analytical tools in medicine for the isolation, separation and quantification of nicotiflorin.</p><p><strong>Conclusion: </strong>Scientific data analysis of different research works revealed the biological importance and therapeutic potential of nicotiflorin in medicine.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"15 1","pages":"2-11"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10394347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Human <i>in vivo</i> Metabolism of SEP-227900 Using the Samples from First-in-Human Study by LC-HRMS/UV and NMR.","authors":"Yu-Luan Chen,&nbsp;Estela Skende,&nbsp;Armand Gatien Ngounou Wetie,&nbsp;Peter Li-Quan Wang","doi":"10.2174/1872312815666220302161959","DOIUrl":"https://doi.org/10.2174/1872312815666220302161959","url":null,"abstract":"<p><strong>Objective: </strong>The study aims to explore the human in vivo metabolism of SEP-227900 (4H-furo[3, 2-b] pyrrole-carboxylic acid, m.w 151.03), a D-amino-acid oxidase (DAAO) inhibitor, by using plasma and urine samples from first-in-human study.</p><p><strong>Methods: </strong>The human plasma and urine samples were from a single dose cohort that consisted of 9 healthy male volunteers each received an 80- mg dose of SEP-227900 orally. The pooled pre-dose urine and the pooled 0-24 h urine sample were created across 9 subjects by equal volume. Plasma samples were pooled by equal volume across 9 subjects to obtain 0-12 h plasma for metabolite searching, and also pooled by timepoints across 9 subjects to obtain 0.5, 5, and 12-h plasma for semi-quantitation. The plasma was de-proteinized by acetonitrile (1:3 v/v plasma-acetonitrile), then the supernatant was dried down, reconstituted, and injected for LC-HRMS/UV analysis. The urine sample was just simply centrifuged before analysis. LC-HRMS/UV was utilized to search predictable and unknown metabolites and estimate their relative abundances. Accurate mass measurement by Orbitrap-MS and MS/MS was used for metabolite identification. Chromatographic separation was achieved on a MACMOD AQ C₈ column (250 × 4.6 mm, 5-μm) with a gradient mobile phase (A: 10 mM NH₄Ac; B: acetonitrile; flowrate: 0.700 ml/min) for a total run-time of 65 min. The definite position in the molecule for the glucuronidation metabolism was characterized by the detected migration phenomenon, methylation with diazomethane (CH₂N₂), and NMR.</p><p><strong>Results: </strong>Unchanged parent drug and four metabolite peaks were detected in humans: M1 was a mono-oxidative metabolite of SEP-227900; M2 was a glucuronide conjugate of SEP-227900; M3 was a glycine conjugate of SEP-227900; M4 was a glycine conjugate of M1. The specific position of the oxidation in M1 solely based on the mass spectral (MS and MS/MS) data was not identified. However, for the major metabolite M2, the acyl glucuronidation was unambiguously determined through multiple pieces of experimental evidence such as the observation of a migration pattern, mono-methylation by diazomethane, and NMR measurement. This determination is of significance related to the safety evaluation of investigational new drug development. The glycine conjugate of SEP-227900, i.e., M3, was found to be the most abundant metabolite in human urine (approximately 3-fold higher level than the glucuronide level). All together (mainly glycine-conjugate and glucuronide), it resulted in greater than 80% of the dosed amount in urine excretion (a separate measurement showed 23% of the dosed amount in urine excretion as the glucuronide).</p><p><strong>Conclusion: </strong>Four metabolites were found in humans: SEP-227900-glycine conjugate, SEP- 227900-glucuronide, mono-oxidative metabolite, and its consequent glycine conjugate. The glucuronide metabolite wa","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"15 1","pages":"38-50"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10453428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of P34S, G169R, R296C, and S486T Substitutions in Ligand Access and Catalysis for Cytochrome P450 2D6 Allelic Variants CYP2D6*14A and CYP2D6*14B.","authors":"Amelia Nathania Dong,&nbsp;Nafees Ahemad,&nbsp;Yan Pan,&nbsp;Uma Devi Palanisamy,&nbsp;Beow Chin Yiap,&nbsp;Chin Eng Ong","doi":"10.2174/1872312815666220113125232","DOIUrl":"https://doi.org/10.2174/1872312815666220113125232","url":null,"abstract":"<p><strong>Background: </strong>Genetic polymorphism of cytochrome P450 (CYP) contributes to variability in drug metabolism, clearance, and response. This study aimed to investigate the functional and molecular basis for altered ligand binding and catalysis in CYP2D6*14A and CYP2D6*14B, two unique alleles common in the Asian population.</p><p><strong>Methods: </strong>CYP proteins expressed in Escherichia coli were studied using the substrate 3-cyano-7- ethoxycoumarin (CEC) and inhibitor probes (quinidine, fluoxetine, paroxetine, terbinafine) in the enzyme assay. Computer modelling was additionally used to create three-dimensional structures of the CYP2D6*14 variants.</p><p><strong>Results: </strong>Kinetics data indicated significantly reduced intrinsic clearance in CYP2D6*14 variants, suggesting that P34S, G169R, R296C, and S486T substitutions worked cooperatively to alter the conformation of the active site that negatively impacted the deethylase activity of CYP2D6. For the inhibition studies, IC50 values decreased in quinidine, paroxetine, and terbinafine but increased in fluoxetine, suggesting a varied ligand-specific susceptibility to inhibition. Molecular docking further demonstrated the role of P34S and R296C in altering access channel dimensions, thereby affecting ligand access and binding and subsequently resulting in varied inhibition potencies.</p><p><strong>Conclusion: </strong>In summary, the differential selectivity of CYP2D6*14 variants for the ligands (substrate and inhibitor) was governed by the alteration of the active site and access channel architecture induced by the natural mutations found in the alleles.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"15 1","pages":"51-63"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10392826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In Vitro</i> Inhibitory Effects of Agarwood Tea (<i>Aquilaria malaccensis</i> Lamk) Aqueous Extract on Human Cytochrome P450 (CYP) Enzyme Activities.","authors":"Pan Yan,&nbsp;Ung Yee Tze,&nbsp;Premika A/P R Jagadish,&nbsp;Lim Kuan Hon,&nbsp;Lamia Noushin Sadeque Chowdhury,&nbsp;Shang Tao,&nbsp;Ong Chin Eng","doi":"10.2174/1872312815666220707114744","DOIUrl":"https://doi.org/10.2174/1872312815666220707114744","url":null,"abstract":"<p><strong>Background: </strong>Agarwood tea derived from Aquilaria malaccensis Lamk is becoming an increasingly popular herbal drink that is said to have multiple health benefits. Co-administration of this tea and clinical used drugs is possible, but it increases the risk of drug-herb interactions.</p><p><strong>Objective: </strong>This in vitro study investigated the inhibitory effects of agarwood tea aqueous extract on the eight major human drug-metabolising cytochrome P450 (CYP) enzyme activities.</p><p><strong>Methods: </strong>High-throughput fluorescence-based Vivid® CYP450 screening kits were employed to obtain the enzyme activities before and after incubation with agarwood tea aqueous extract.</p><p><strong>Results: </strong>Agarwood aqueous extract potently inhibited CYP2C9, CYP2D6, and CYP3A4 activities with Ki values of 5.1, 34.5, and 20.3μg/ml, respectively. The most likely inhibition mode responsible for these inhibitions was non-competitive inhibition. On the other hand, at 1000μg/ml, agarwood tea aqueous extract negligibly inhibited CYP1A2, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 activities.</p><p><strong>Conclusion: </strong>These findings can be used to design additional in vitro investigations using clinical relevant drug substrates for CYP2C9, CYP2D6, and CYP3A4. Subsequently, future studies can be conducted to determine potential interactions between agarwood tea aqueous extract and CYP using in vivo models.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"15 3","pages":"178-191"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10399172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the Gut Microbiome in Diabetes and Cardiovascular Diseases Including Restoration and Targeting Approaches- A Review.","authors":"Alka Ahuja,&nbsp;Saraswathy Mp,&nbsp;Nandakumar S,&nbsp;Arul Prakash F,&nbsp;Gurpreet Kn,&nbsp;Dhanalekshmi Um","doi":"10.2174/2949681015666220615120300","DOIUrl":"https://doi.org/10.2174/2949681015666220615120300","url":null,"abstract":"<p><p>Metabolic diseases, including cardiovascular diseases (CVD) and diabetes, have become the leading cause of morbidity and mortality worldwide. Gut microbiota appears to play a vital role in human disease and health, according to recent scientific reports. The gut microbiota plays an important role in sustaining host physiology and homeostasis by creating a cross-talk between the host and microbiome via metabolites obtained from the host's diet. Drug developers and clinicians rely heavily on therapies that target the microbiota in the management of metabolic diseases, and the gut microbiota is considered the biggest immune organ in the human body. They are highly associated with intestinal immunity and systemic metabolic disorders like CVD and diabetes and are reflected as potential therapeutic targets for the management of metabolic diseases. This review discusses the mechanism and interrelation between the gut microbiome and metabolic disorders. It also highlights the role of the gut microbiome and microbially derived metabolites in the pathophysiological effects related to CVD and diabetes. It also spotlights the reasons that lead to alterations of microbiota composition and the prominence of gut microbiota restoration and targeting approaches as effective treatment strategies in diabetes and CVD. Future research should focus onunderstanding the functional level of some specific microbial pathways that help maintain physiological homeostasis, multi-omics, and develop novel therapeutic strategies that intervene with the gut microbiome for the prevention of CVD and diabetes that contribute to a patient's well-being.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"15 3","pages":"133-149"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10399169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Practical Application of Rodent Transporter Knockout Models to Assess Brain Penetration in Drug Discovery.","authors":"Elin Eneberg,&nbsp;Christopher R Jones,&nbsp;Thomas Jensen,&nbsp;Kristine Langthaler,&nbsp;Christoffer Bundgaard","doi":"10.2174/1872312815666220222091032","DOIUrl":"https://doi.org/10.2174/1872312815666220222091032","url":null,"abstract":"<p><strong>Background and objective: </strong>Compound X is a drug candidate for the treatment of neurodegenerative diseases. Its brain distribution was evaluated as part of the lead identification and optimization activities undertaken in early drug discovery.</p><p><strong>Methods: </strong>The brain distribution of compound X was studied in genetic transporter knockout rodent models, in vivo models with a chemical inhibitor, and in vitro transporter cell systems.</p><p><strong>Results: </strong>Compound X was found to be a substrate for human Breast Cancer-Resistance Protein (BCRP) in vitro (efflux ratio 8.1) and rodent Bcrp in vivo (Kp, uuKO/Kp, uuWT = 0.15/0.057 = 2.7, p< 0.05) but not a substrate for human P-glycoprotein (P-gp) in vitro (efflux ratio 1.0) nor rodent P-gp in vivo (Kp, uuKO/Kp, uuWT = 0.056/ 0.051 = 1.1, p> 0.05). When both transporters were knocked out in vivo, Kp, uu increased to 0.51±0.02. A similar pattern observed across compounds with related chemistry corroborating the structure-activity relationship.</p><p><strong>Conclusion: </strong>While in vitro assays showed compound X to be a substrate for human BCRP and not P-gp, in vivo studies indicated a synergistic effect between rodent efflux transporters. However, this only accounted for ~50% of restricted BBB-transport, suggesting involvement of other efflux transporters. Considering Kp, uu as a key criterion for assessing the technical quality of CNS candidates before progression into clinical development, it is important to identify relevant screening assays for a better understanding of low Kp, uu and brain distribution in pre-clinical models for translation to humans.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":"15 1","pages":"12-21"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10759144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}