placeholder
and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Document type
Language
Year
  • 1
    Language: English
    In: Nature materials, 2019-05-01, Vol.18 (5), p.418-422
    Description: At the recent Artificial Intelligence Applications in Biopharma Summit in Boston, USA, a panel of scientists from industry who work at the interface of machine learning and pharma discussed the diverging opinions on the past, present and future role of AI for ADME/Tox in drug discovery and development.
    Subject(s): Algorithms ; Artificial Intelligence ; Chemistry ; Chemistry, Physical ; Computational Biology - methods ; Computer Simulation ; Congresses as Topic ; Decision Making ; Deep Learning ; Drug Design ; Drug Discovery ; Humans ; Machine Learning ; Materials Science ; Materials Science, Multidisciplinary ; Mitochondria ; Pharmacokinetics ; Physical Sciences ; Physics ; Physics, Applied ; Physics, Condensed Matter ; Science & Technology ; Technology ; Technology, Pharmaceutical - methods
    ISSN: 1476-1122
    E-ISSN: 1476-4660
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Get It Now
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: Pharmacology research & perspectives, 2020-10, Vol.8 (5), p.e00645-n/a
    Description: We have previously reported successful isolation and cryopreservation of human intestinal mucosa (CHIM) with retention of viability and drug metabolizing enzyme activities. Here we report the results of the quantification of drug metabolizing enzyme activities in CHIM from different regions of the small intestines from 14 individual donors. CHIM were isolated from the duodenum, jejunum, and ileum of 10 individuals, and from 10 consecutive 12‐inch segments starting from the pyloric sphincter of human small intestines from four additional individuals. P450 and non‐P450 drug metabolizing enzyme activities (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, UGT, SULT, FMO, MAO, AO, NAT1, and NAT2) were quantified via incubation with pathway‐selective substrates. Quantifiable activities were observed for all pathways except for CYP2A6. Comparison of the duodenum, jejunum, and ileum in 10 donors shows jejunum had higher activities for CYP2C9, CYP3A, UGT, SULT, MAO, and NAT1. Further definition of regional variations with CHIM from ten 12‐inch segments of the proximal small intestine shows that the segments immediately after the first 12‐inch segment (duodenum) had the highest activity for most of the drug metabolizing enzymes but with substantial differences among the four donors. Our overall results demonstrate that there are substantial individual differences in drug metabolizing enzymes and that jejunum, especially the regions immediately after the duodenum, had the highest drug metabolizing enzyme activities.
    Subject(s): Bioavailability ; CHIM ; Cryopreservation ; duodenum ; enteric drug metabolism ; Enzymes ; Head injuries ; human intestine ; ileum ; jejunum ; Laboratories ; Metabolism ; Metabolites ; Regions ; Small intestine
    ISSN: 2052-1707
    E-ISSN: 2052-1707
    Source: Academic Search Ultimate
    Source: PubMed Central
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: Drug metabolism and disposition, 2018-07, Vol.46 (7), p.943-952
    Description: To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( = 27) or hepatitis C (HCV, = 30) cirrhotic versus noncirrhotic (control) livers ( = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was 〈25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
    Subject(s): Adult ; Aged ; Alcohol Dehydrogenase - metabolism ; Alcoholics ; Carboxylesterase - metabolism ; Cytochrome P-450 CYP1A2 - metabolism ; Female ; Hepatitis C - metabolism ; Humans ; Inactivation, Metabolic - physiology ; Liver - metabolism ; Liver Cirrhosis - metabolism ; Liver Cirrhosis, Alcoholic - metabolism ; Male ; Middle Aged ; Morphine - pharmacokinetics ; Proteomics - methods ; Young Adult ; Zidovudine - pharmacokinetics
    ISSN: 0090-9556
    E-ISSN: 1521-009X
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    Language: English
    In: Journal of pharmaceutical sciences, 2012-02, Vol.101 (2), p.838-851
    Description: In vitro–in vivo extrapolation (IVIVE) is an important method for estimating the hepatic metabolic clearance (CL) of drugs. This study highlights a problematic area observed when using microsomal data to predict in vivo CL of drugs that are highly bound to plasma proteins, and further explores mechanisms for human CL predictions by associating additional processes to IVIVE disconnect. Therefore, this study attempts to develop a novel IVIVE calculation method, which consists of adjusting the binding terms in a well-stirred liver model. A comparative assessment between the IVIVE method proposed here and previously published methods of Obach (1999. Drug Metab Dispos 27:1350–1359) and Berezhkovskiy (2010. J Pharm Sci 100:1167–1783) was also performed. The assessment was confined by the availability of measured in vitro and in vivo data in humans for 25 drugs highly bound to plasma proteins, for which it can be assumed that metabolism is the major route of elimination. Here, we argue that a difference in drug ionization and binding proteins such as albumin (AL) and alpha-1-acid glycoprotein (AAG) in plasma and liver also needs to be considered in IVIVE based on mechanistic studies. Therefore, converting unbound fraction in plasma to liver essentially increased the predicted CL values, which resulted in much more accurate estimates of in vivo CL as compared with the other IVIVE methods tested. The impact on CL estimate was more apparent for drugs binding to AL than to AAG. This is a mechanistic rational for explaining a considerable proportion of the divergence between previously estimated and observed CL values. Human CL was predicted within 1.5-fold, twofold, and threefold of the observed CL for 84%, 96%, and 100% of the compounds, respectively. Overall, this study demonstrates a significant improvement in the mechanism-based prediction of metabolic CL for these 25 highly bound drugs from in vitro data determined with microsomes, which should facilitate the application of physiologically based pharmacokinetic (PBPK) models in drug discovery and development. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association.
    Subject(s): computational ADME ; disposition ; hepatic clearance ; Humans ; In Vitro Techniques ; in vitro-in vivo extrapolation ; IVIVE ; Liver - metabolism ; metabolic clearance ; microsomes ; Models, Theoretical ; PBPK modeling ; Pharmacokinetics ; unbound fraction
    ISSN: 0022-3549
    E-ISSN: 1520-6017
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Drug metabolism and disposition, 2019-04-01, Vol.47 (4), p.350-357
    Description: Suspended (SH), plated (PH), and sandwich-cultured hepatocytes (SCH) are commonly used models to predict in vivo transporter-mediated hepatic uptake (SH or PH) or biliary (SCH) clearance of drugs. When doing so, the total and the plasma membrane abundance (PMA) of transporter are assumed not to differ between hepatocytes and liver tissue (LT). This assumption has never been tested. In this study, we tested this assumption by measuring the total and PMA of the transporters in human hepatocyte models versus LT (total only) from which they were isolated. Total abundance of OATP1B1/2B1/1B3, OCT1, and OAT2 was not significantly different between the hepatocytes and LT. The same was true for the PMA of these transporters across the hepatocyte models. In contrast, total abundance of the sinusoidal efflux transporter, MRP3, and the canalicular efflux transporters, MRP2 and P-gp, was significantly greater (P 〈 0.05) in SCH versus LT. Of the transporters tested, only the percentage of PMA of OATP1B1, P-gp, and MRP3, in SCH (82.8% +/- 7.3%, 57.5% +/- 10.9%, 69.3% +/- 5.7%) was significantly greater (P 〈 0.05) than in SH (73.3% +/- 6.4%, 27.4% +/- 6.4%, 53.6% +/- 4.1%). If the transporters measured in the plasma membrane are functional and the PMA in SH is representative of that in LT, these data suggest that SH, PH, and SCH will result in equal prediction of hepatic uptake clearance of drugs mediated by the transporters tested above. However, SCH will predict higher sinusoidal efflux and biliary clearance of drugs if the change in PMA of these transporters is not taken into consideration.
    Subject(s): Biological Transport - physiology ; Biotinylation - physiology ; Cell Culture Techniques - methods ; Cell Membrane - metabolism ; Cells, Cultured ; Hepatocytes - metabolism ; Humans ; Life Sciences & Biomedicine ; Liver - metabolism ; Membrane Transport Proteins - metabolism ; Organic Anion Transporters - metabolism ; Pharmacology & Pharmacy ; Proteomics - methods ; Science & Technology
    ISSN: 0090-9556
    E-ISSN: 1521-009X
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Drug metabolism and disposition, 2018-06, Vol.46 (6), p.865-878
    Description: Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry.
    Subject(s): Animals ; Drug Discovery - standards ; Drug Industry - standards ; Drug Interactions - physiology ; Humans ; Inactivation, Metabolic - physiology ; Pharmaceutical Preparations - metabolism ; United States ; United States Food and Drug Administration
    ISSN: 0090-9556
    E-ISSN: 1521-009X
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: Drug metabolism and disposition, 2018-02, Vol.46 (2), p.189-196
    Description: Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, = 8) and adjacent noncancerous (NC, = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from noninfected, noncirrhotic (control, = 36) and HCV-cirrhotic ( = 30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers. In comparison with control livers, with the exception of NTCP, MRP2, and MATE1, transporter expression decreased in NC (38%-76%) and C (56%-96%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP expression increased (113%), MATE1 expression decreased (58%), and MRP2 expression was unchanged relative to control livers. In C HCV-HCC tissues, NTCP and MRP2 expression decreased (63%, 56%) and MATE1 expression was unchanged relative to control livers. Compared with HCV-cirrhotic livers, aside from NTCP, OCT1, BSEP, and MRP2, transporter expression decreased in NC (41%-71%) and C (54%-89%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP and MRP2 expression increased (362%, 142%), whereas OCT1 and BSEP expression was unchanged. In C HCV-HCC tissues, OCT1 and BSEP expression decreased (90%, 80%) relative to HCV-cirrhotic livers, whereas NTCP and MRP2 expression was unchanged. Expression of OATP2B1, BSEP, MRP2, and MRP3 decreased (56%-72%) in C HCV-HCC tissues in comparison with matched NC tissues ( = 8), but the expression of other transporters was unchanged. These data will be helpful in the future to predict transporter-mediated hepatocellular drug concentrations in patients with HCV-HCC.
    Subject(s): ATP-Binding Cassette Transporters - metabolism ; Carcinoma, Hepatocellular - metabolism ; Chromatography, Liquid - methods ; Female ; Hepatitis C, Chronic - metabolism ; Humans ; Liver - metabolism ; Liver Neoplasms - metabolism ; Male ; Middle Aged ; Multidrug Resistance-Associated Proteins - metabolism ; Organic Anion Transporters - metabolism ; Proteomics - methods ; Tandem Mass Spectrometry - methods
    ISSN: 0090-9556
    E-ISSN: 1521-009X
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    Language: English
    In: Pharmaceutical research, 2016-02-11, Vol.33 (5), p.1204-1219
    Description: Purpose To evaluate an alternative in vitro system which can provide more quantitatively accurate drug drug interaction (DDI) prediction for 10 protein kinase inhibitors for which DDI risk was over-predicted by inhibition data generated in human liver microsomes (HLM). Methods Three cryopreserved human hepatocyte (hHEP) systems: 1) plated hHEPs; 2) hHEPs suspended in Dulbecco’s Modified Eagle Medium (DMEM) and 3) hHEPs suspended in human plasma (plasma hHEPs) were developed to detect CYP3A time dependent inhibition, and the static mechanistic model was used to predict clinical outcomes. Results A general trend was observed in the CYP3A inactivation potency ( k inact / K I, app ) as HLM 〉 plated 〉 DMEM ≥ plasma hHEPs. Using the static mechanistic model, DDIs predicted using parameters estimated from plated, DMEM and plasma hHEPs had 84, 74 and 95% accuracy (out of 19 clinical interaction studies) within 2-fold of the reported interaction, respectively. They demonstrated significant improvement compared to the DDIs predicted using parameters estimated from HLMs where 58% accuracy was obtained. Conclusions Based on 19 DDIs, plasma hHEPs demonstrate a more reliable clinical DDI prediction for 10 protein kinase inhibitors and prototypical CYP3A time dependent inhibitors.
    Subject(s): Biochemistry ; Biochemistry, general ; Biomedical and Life Sciences ; Biomedical Engineering ; Biomedical Engineering and Bioengineering ; Biomedicine ; Comparative analysis ; CYP3A ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 CYP3A Inhibitors - pharmacology ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical - methods ; Drug Interactions ; drug–drug interaction ; Enzyme Assays - methods ; general ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Humans ; kinase inhibitors ; Kinetics ; Medical Law ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; Models, Biological ; Pharmacology/Toxicology ; Pharmacy ; Plasma - drug effects ; Plasma - metabolism ; prediction ; Protein kinases ; Research Paper ; time dependent inhibition ; Yuan (China)
    ISSN: 0724-8741
    E-ISSN: 1573-904X
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: Journal of pharmaceutical sciences, 2012-11, Vol.101 (11), p.4308-4326
    Description: The purpose of this study was to perform a comparative analysis of various in vitro--in vivo extrapolation (IVIVE) methods used for predicting hepatic metabolic clearance (CL) of drugs on the basis of intrinsic CL data determined in microsomes. Five IVIVE methods were evaluated: the “conventional and conventional bias-corrected methods” using the unbound fraction in plasma (fup), the “Berezhkovskiy method” in which the fup is adjusted for drug ionization, the “Poulin et al. method” using the unbound fraction in liver (fuliver), and the “direct scaling method,” which does not consider any binding corrections. We investigated the effects of the following scenarios on the prediction of CL: the use of preclinical or human datasets, the extent of plasma protein binding, the magnitude of CL in vivo, and the extent of drug disposition based on biopharmaceutics drug disposition classification system (BDDCS) categorization. A large and diverse dataset of 139 compounds was collected, including those from the literature and in house from Genentech. The results of this study confirm that the Poulin et al. method is robust and showed the greatest accuracy as compared with the other IVIVE methods in the majority of prediction scenarios studied here. The difference across the prediction methods is most pronounced for (a) albumin-bound drugs, (b) highly bound drugs, and (c) low CL drugs. Predictions of CL showed relevant interspecies differences for BDDCS class 2 compounds; the direct scaling method showed the greatest predictivity for these compounds, particularly for a reduced dataset in rat that have unexpectedly high CL in vivo. This result is a reflection of the direct scaling method's natural tendency to overpredict the true metabolic CL. Overall, this study should facilitate the use of IVIVE correlation methods in physiologically based pharmacokinetics (PBPK) model.
    Subject(s): Animals ; Biological and medical sciences ; Blood proteins ; clearance ; Comparative analysis ; computational ADME ; disposition ; Drugs ; General pharmacology ; Humans ; in vitro-in vivo correlation ; in vitro-in vivo extrapolation ; IVIVE ; Liver - metabolism ; Medical sciences ; Methods ; microsomes ; PBPK modeling ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacokinetics ; Pharmacology. Drug treatments ; Protein binding ; unbound fraction ; Usage
    ISSN: 0022-3549
    E-ISSN: 1520-6017
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Cancer chemotherapy and pharmacology, 2016-05-06, Vol.78 (1), p.41-49
    Description: Purpose The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics. Methods Cohorts included a control arm ( n  = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n  = 24); itraconazole 200 mg ( n  = 22); or fluconazole 400 mg ( n  = 22). Results Area under the vismodegib concentration–time curve from zero to 24 h (AUC 0–24h ) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC 0–24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib. Conclusion The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug–drug interaction. ClinicalTrials.gov Identifier NCT01772290.
    Subject(s): Anilides - administration & dosage ; Anilides - pharmacokinetics ; Area Under Curve ; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Cancer Research ; Clinical drug–drug interaction ; Clinical pharmacology ; CYP inhibitors ; Cytochrome P-450 ; Cytochrome P-450 CYP2C9 Inhibitors - administration & dosage ; Cytochrome P-450 CYP2C9 Inhibitors - pharmacology ; Cytochrome P-450 CYP3A Inhibitors - administration & dosage ; Cytochrome P-450 CYP3A Inhibitors - pharmacology ; Drug Interactions ; Female ; Fluconazole - administration & dosage ; Fluconazole - pharmacology ; Humans ; Hydrogen-Ion Concentration ; Itraconazole - administration & dosage ; Itraconazole - pharmacology ; Medicine ; Medicine & Public Health ; Oncology ; Original ; Original Article ; P-glycoprotein inhibitor ; Pharmacokinetic ; Pharmacology/Toxicology ; Proton Pump Inhibitors - administration & dosage ; Proton Pump Inhibitors - pharmacology ; Proton-pump inhibitor ; Pyridines - administration & dosage ; Pyridines - pharmacokinetics ; Rabeprazole - administration & dosage ; Rabeprazole - pharmacology ; Solubility
    ISSN: 0344-5704
    E-ISSN: 1432-0843
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...