12 results on '"Fancher, R. Marcus"'
Search Results
2. A convenient strategy to overcome interference in LC-MS/MS analysis: Application in a microdose absolute bioavailability study
- Author
-
Yuan, Long, Huang, Christine, Liu-Kreyche, Peggy, Voronin, Kimberly, Fancher, R. Marcus, Allentoff, Alban, Zheng, Naiyu, Iyer, Ramaswamy, Zhu, Li, Pillutla, Renuka, and Ji, Qin C.
- Published
- 2019
- Full Text
- View/download PDF
3. Investigation of the “true” extraction recovery of analytes from multiple types of tissues and its impact on tissue bioanalysis using two model compounds
- Author
-
Yuan, Long, Ma, Li, Dillon, Lisa, Fancher, R. Marcus, Sun, Huadong, Zhu, Mingshe, Lehman-McKeeman, Lois, Aubry, Anne-Françoise, and Ji, Qin C.
- Published
- 2016
- Full Text
- View/download PDF
4. Development of a Canine Model to Enable the Preclinical Assessment of Ph-dependent Absorption of Test Compounds
- Author
-
Fancher, R. Marcus, Zhang, Hongjian, Sleczka, Bogdan, Derbin, George, Rockar, Richard, and Marathe, Punit
- Published
- 2011
- Full Text
- View/download PDF
5. Increasing the Reuse of Protein Non-Naïve Nonhuman Primates in Pharmaceutical Drug Discovery and Development: An Overview and Industry Position on the Challenges and Benefits.
- Author
-
Mattis, Charles, Bratcher, Natalie, Burns, Monika, Carosino, Christopher, de Zafra, Christina, Fancher, R. Marcus, Georgi, Katrin, Graff, Candace, Hukkanen, Renee R., Johnson, Colena, Lao, Yanbin, Lange, Amber, Lee, Donna, Lepherd, Michelle, Maguire, Sean, Malisauskas, Mantas, Manuel, Melinda, Miranda, Sonia, Reed, Lori, and Santos, Rosemary
- Subjects
DRUG discovery ,CONTRACT research organizations ,DRUG development ,DRUGS ,PHARMACEUTICAL biotechnology - Abstract
The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists. This paper's content reflects the consolidated opinion of the WG members and the questionnaire responses on the subject of NHP reuse within nonclinical programs at all stages of research and development. Many of the pharmaceutical companies represented in the working group or participating in the questionnaire have already achieved some level of NHP reuse in their nonclinical programs, but the survey results suggested that there is significant potential to increase NHP reuse further and a need to understand the considerations involved in reuse more clearly. The WG has also focused carefully on the inherent concerns and risks of implementing protein non-naive NHP reuse and has evaluated the best methods of risk assessment and decision-making. This paper presents a discussion on the challenges and opportunities surrounding protein non-naïve NHP reuse and aims to stimulate further industry dialogue on the subject and provide guidance for pharmaceutical companies to establish roadmaps and decision trees enabling increased protein non-naïve NHP reuse. In addition, this paper represents a solid basis for collaborative engagement between pharmaceutical and biotechnology companies with contract research organizations (CROs) to discuss how the availability of protein non-naïve NHP within CROs can be better leveraged for their use within nonclinical studies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
6. Utility of in situ sodium alginate/karaya gum gels to facilitate gastric retention in rodents
- Author
-
Foster, Kimberly A., Morgen, Mike, Murri, Brice, Yates, Ian, Fancher, R. Marcus, Ehrmann, Jon, Gudmundsson, Olafur S., and Hageman, Michael J.
- Subjects
- *
SODIUM alginate , *GASTRIC acid , *LABORATORY rodents , *BARIUM sulfate , *FEASIBILITY studies , *SPRAGUE Dawley rats - Abstract
Abstract: Target validation or demonstration of efficacy requires adequate in vivo exposure of tool molecules to determine their activity in order to validate the model or show the potential usefulness of the pharmacophore. Early discovery work is often carried out with compounds which possess undesirable PK properties in small rodents where the discovery formulation scientist is often forced to dose 2–4 times per day. Gastric retentive formulations in small rodents (rats/mice) could enable increased duration of exposure for compounds with narrow absorption windows or increased residence time for compounds with targets located in the GI tract. The aim of this work is to establish an easily administered gastric retentive gel for rodents in situ using a mixture of sodium alginate and karaya gum. Feasibility studies were conducted in Sprague-Dawley rats using barium sulfate as a radio-opaque tracer. The results show that gastric retention of barium was achieved for rats dosed with the gel formulation relative to a barium suspension. The gastric residence time of the gel varied from 1h to >8h (n =3). The data suggest that sodium alginate/karaya gum gels may be a useful tool to achieve gastric retention in rodent studies. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
7. Metabolomic Profiling and Drug Interaction Characterization Reveal Riboflavin As a Breast Cancer Resistance Protein-Specific Endogenous Biomarker That Demonstrates Prediction of Transporter Activity In Vivo.
- Author
-
Zhang Y, Shipkova PA, Warrack BM, Nelson DM, Wang L, Huo R, Chen J, Panfen E, Chen XQ, Fancher RM, Ruan Q, Christopher LJ, Xue Y, Sinz M, and Shen H
- Subjects
- Humans, Mice, Animals, Female, ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, ATP-Binding Cassette Transporters metabolism, Neoplasm Proteins metabolism, ATP Binding Cassette Transporter, Subfamily B metabolism, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Mice, Knockout, Biomarkers metabolism, Drug Interactions, Brain metabolism, Breast Neoplasms metabolism
- Abstract
Advancement of endogenous biomarkers for drug transporters as a tool for assessing drug-drug interactions (DDIs) depends on initial identification of biomarker candidates and relies heavily on biomarker validation and its response to reference inhibitors in vivo. To identify endogenous biomarkers of breast cancer resistance protein (BCRP), we applied metabolomic approaches to profile plasma from Bcrp
-/- , multidrug resistance protein (Mdr)1a/1b-/- , and Bcrp/Mdr1a/1b-/- mice. Approximately 130 metabolites were significantly altered in Bcrp and P-glycoprotein (P-gp) knockout mice, indicating numerous metabolite-transporter interactions. We focused on BCRP-specific substrates and identified riboflavin, which was significantly elevated in the plasma of Bcrp single- and Bcrp/P-gp double- but not P-gp single-knockout mice. Dual BCRP/P-gp inhibitor elacridar caused a dose-dependent increase of the area under the plasma concentration-time curve ( AUC ) of riboflavin in mice (1.51- and 1.93-fold increases by 30 and 150 mg/kg elacridar, respectively). In three cynomolgus monkeys, we observed approximately 1.7-fold increases in the riboflavin concentrations caused by ML753286 (10 mg/kg), which correlated well with the increase of sulfasalazine, a known BCRP probe in monkeys. However, the BCRP inhibitor had no effect on isobutyryl carnitine, arginine, or 2-arachidonoyl glycerol levels. Additionally, clinical studies on healthy volunteers indicated low intrasubject and intermeal variability of plasma riboflavin concentrations. In vitro experiments using membrane vesicles demonstrated riboflavin as a select substrate of monkey and human BCRP over P-gp. Collectively, this proof-of-principle study indicates that riboflavin is a suitable endogenous probe for BCRP activity in mice and monkeys and that future investigation of riboflavin as a blood-based biomarker of human BCRP is warranted. SIGNIFICANCE STATEMENT: Our results identified riboflavin as an endogenous biomarker candidate of BCRP. Its selectivity, sensitivity, and predictivity regarding BCRP inhibition have been explored. The findings of this study highlight riboflavin as an informative BCRP plasma biomarker in animal models. The utility of this biomarker requires further validation by evaluating the effects of BCRP inhibitors of different potencies on riboflavin plasma concentrations in humans. Ultimately, riboflavin may shed light on the risk assessment of BCRP DDIs in early clinical trials., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2023
- Full Text
- View/download PDF
8. Absence of OATP1B (Organic Anion-Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression.
- Author
-
Zhang Y, Chen C, Chen SJ, Chen XQ, Shuster DJ, Puszczalo PD, Fancher RM, Yang Z, Sinz M, and Shen H
- Subjects
- Animals, Biomarkers blood, Female, Hydroxycholesterols blood, Intestine, Small drug effects, Intestine, Small metabolism, Kidney drug effects, Kidney metabolism, Liver drug effects, Liver metabolism, Macaca fascicularis, Male, Rifampin administration & dosage, Rifampin blood, Solute Carrier Organic Anion Transporter Family Member 1B3 genetics, Coproporphyrins blood, Gene Expression drug effects, Rifampin pharmacology, Solute Carrier Organic Anion Transporter Family Member 1B3 biosynthesis
- Abstract
Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4 β -hydroxycholesterol (4 β HC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4 β HC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2020
- Full Text
- View/download PDF
9. Absorption and Disposition of Coproporphyrin I (CPI) in Cynomolgus Monkeys and Mice: Pharmacokinetic Evidence to Support the Use of CPI to Inform the Potential for Organic Anion-Transporting Polypeptide Inhibition.
- Author
-
Gu X, Wang L, Gan J, Fancher RM, Tian Y, Hong Y, Lai Y, Sinz M, and Shen H
- Subjects
- Administration, Intravenous, Administration, Oral, Animals, Area Under Curve, Biological Availability, Biomarkers analysis, Biomarkers metabolism, Coproporphyrins analysis, Coproporphyrins pharmacokinetics, Cyclosporine administration & dosage, Cyclosporine pharmacokinetics, Drug Evaluation, Preclinical methods, Drug Interactions, Half-Life, Intestinal Absorption, Kidney drug effects, Kidney metabolism, Liver drug effects, Liver metabolism, Liver-Specific Organic Anion Transporter 1 antagonists & inhibitors, Macaca fascicularis, Male, Mice, Rifampin administration & dosage, Tissue Distribution, Coproporphyrins metabolism, Liver-Specific Organic Anion Transporter 1 metabolism
- Abstract
Despite a recent expansion in the recognition of the potential utility of coproporphyrin (CP) as an endogenous biomarker of organic anion-transporting polypeptide (OATP) 1B activity, there have been few detailed studies of CP's pharmacokinetic behavior and an overall poor understanding of its pharmacokinetic fate from tissues and excretion. Here, we describe the pharmacokinetics of octadeuterium-labeled coproporphyrin I (CPI-d8) in cynomolgus monkeys following oral and intravenous administration. CPI-d8 has a half-life and bioavailability of 7.6 hours and 3.2%, respectively. Cynomolgus monkeys received oral cyclosporin A (CsA) at 4, 20, and 100 mg/kg which yielded maximum blood concentrations ( C
max ) and area under the plasma concentration-time curve (AUC) values of 0.19, 2.5, and 3.8 µM, and 2.7, 10.5, and 26.6 µM·h, respectively. The apparent CsA-dose dependent increase in the AUC ratio of CPI-d8 (1.8, 6.2, and 10.5), CPI (1.1, 1.4, and 4.4), and CPIII (1.1, 1.8, and 4.6) at 4, 20, and 100 mg, respectively. In contrast, the plasma concentrations of CPI and CPIII were generally not affected by intravenous administration of the renal organic anion and cation transporter inhibitors (probenecid and pyrimethamine, respectively). In addition, tritium-labeled coproporphyrin I ([3 H]CPI) showed specific and rapid distribution to the liver, intestine, and kidney after an intravenous dose in mice using quantitative whole-body autoradiography. Rifampin markedly reduced the liver and intestinal uptake of [3 H]CPI while increasing the kidney uptake. Taken together, these results suggest that hepatic OATP considerably affects the disposition of CPI in animal models, indicating CPI is a sensitive and selective endogenous biomarker of OATP inhibition. SIGNIFICANCE STATEMENT: This study demonstrated that coproporphyrin I (CPI) has favorable oral absorption, distribution, and elimination profiles in monkeys and mice as an endogenous biomarker. It also demonstrated its sensitivity and selectivity as a probe of organic anion-transporting polypeptide (OATP) 1B activity. The study reports, for the first time, in vivo pharmacokinetics, tissue distribution, sensitivity, and selectivity of CPI as an OATP1B endogenous biomarker in animals. The data provide preclinical support for exploration of its utility as a sensitive and selective circulating OATP biomarker in humans., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2020
- Full Text
- View/download PDF
10. Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement.
- Author
-
Li W, Zhao W, Liu X, Huang X, Lopez OD, Leet JE, Fancher RM, Nguyen V, Goodrich J, Easter J, Hong Y, Caceres-Cortes J, Chang SY, Ma L, Belema M, Hamann LG, Gao M, Zhu M, Shu YZ, Humphreys WG, and Johnson BM
- Subjects
- Animals, Bile metabolism, Carbamates, Chromatography, High Pressure Liquid methods, Cytochrome P-450 Enzyme System metabolism, Dogs, Haplorhini, Hepatocytes metabolism, Humans, Macaca fascicularis, Magnetic Resonance Spectroscopy methods, Male, Mass Spectrometry methods, Mice, Mice, Inbred BALB C, Microsomes, Liver metabolism, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Valine analogs & derivatives, Biotransformation physiology, Imidazoles metabolism, Pyrrolidines metabolism
- Abstract
Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2016
- Full Text
- View/download PDF
11. Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation.
- Author
-
Shen H, Liu T, Jiang H, Titsch C, Taylor K, Kandoussi H, Qiu X, Chen C, Sukrutharaj S, Kuit K, Mintier G, Krishnamurthy P, Fancher RM, Zeng J, Rodrigues AD, Marathe P, and Lai Y
- Subjects
- Animals, Cell Line, Drug Interactions physiology, HEK293 Cells, Humans, Kinetics, Macaca fascicularis, Metformin metabolism, Pyrimethamine metabolism, Cations metabolism, Kidney metabolism, Organic Cation Transport Proteins metabolism
- Abstract
Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 ± 0.38, 0.17 ± 0.04, and 0.25 ± 0.04 µM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 ± 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitro-in vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2016
- Full Text
- View/download PDF
12. Evaluation of rosuvastatin as an organic anion transporting polypeptide (OATP) probe substrate: in vitro transport and in vivo disposition in cynomolgus monkeys.
- Author
-
Shen H, Su H, Liu T, Yao M, Mintier G, Li L, Fancher RM, Iyer R, Marathe P, Lai Y, and Rodrigues AD
- Subjects
- Animals, Bile metabolism, Biological Transport drug effects, Cyclosporine pharmacology, Feces chemistry, Fluorobenzenes pharmacokinetics, Fluorobenzenes urine, HEK293 Cells, Humans, Isotope Labeling, Macaca fascicularis, Male, Molecular Probes pharmacokinetics, Molecular Probes urine, Organic Anion Transporters, Sodium-Dependent metabolism, Pyrimidines pharmacokinetics, Pyrimidines urine, Rosuvastatin Calcium, Species Specificity, Sulfonamides pharmacokinetics, Sulfonamides urine, Symporters metabolism, Fluorobenzenes metabolism, Molecular Probes metabolism, Organic Anion Transporters metabolism, Pyrimidines metabolism, Sulfonamides metabolism
- Abstract
Organic anion transporting polypeptides (OATPs) mediate hepatic drug uptake and serve as the loci of drug-drug interactions (DDIs). Consequently, there is a major need to develop animal models and refine in vitro-in vivo extrapolations. Therefore, the in vivo disposition of a model OATP substrate, [(3)H]rosuvastatin (RSV), was studied in the cynomolgus monkey and reported for the first time. After monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (mean total recovery of radioactivity of 103.6%). Forty-two percent of the RSV dose was recovered in urine and bile, and the elimination pathways were similar to those reported for human subjects; 61.7%, 39.0%, and 2.9% of the dose was recovered in the feces, bile, and urine, respectively. The high levels of unchanged RSV recovered in urine and bile (26% of the dose) and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion. Also, for the first time, the in vitro inhibitory potential of cyclosporin A (CsA) toward cynomolgus monkey OATPs and sodium-taurocholate cotransporting polypeptide was studied in vitro (primary hepatocytes and transporter-transfected cells). It is concluded that one can study the CsA-RSV DDI in the cynomolgus monkey. For example, the in vitro IC50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC0-inf (6.3-fold) and Cmax (10.2-fold) with CsA (100 mg/kg) was similar to that reported for humans. The results further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.