scholarly journals Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability

2015 ◽  
Vol 465 (3) ◽  
pp. 479-488 ◽  
Author(s):  
Colin J. Henderson ◽  
Lesley A. McLaughlin ◽  
Maria Osuna-Cabello ◽  
Malcolm Taylor ◽  
Ian Gilbert ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Bioavailability ◽  
Drug Disposition ◽  
Single Agent ◽  
Cre Recombinase ◽  
Drug Metabolizing Enzymes ◽  
Relative Role ◽  
Metabolizing Enzymes ◽  
Gut Metabolism

We describe a mouse model where the functions of key drug-metabolizing enzymes are deleted in liver or liver and gut by application of a single agent, allowing the relative role of each tissue in drug disposition to be established.

Influence of diet supplementation with green tea extract on drug-metabolizing enzymes in a mouse model of monosodium glutamate-induced obesity

2015 ◽  
Vol 55 (1) ◽  
pp. 361-371 ◽  
Author(s):  
Iva Boušová ◽  
Petra Matoušková ◽  
Hana Bártíková ◽  
Barbora Szotáková ◽  
Veronika Hanušová ◽  
...  
Keyword(s):  
Mouse Model ◽  
Green Tea ◽  
Monosodium Glutamate ◽  
Green Tea Extract ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Tea Extract ◽  
Diet Supplementation

Role of Citrus Limonoid as a Possible Bioavailability Enhancer

2020 ◽  
Vol 859 ◽  
pp. 132-138
Author(s):  
Nusara Piyapolrungroj ◽  
Panadda Phattanawasin ◽  
Uthai Sotanaphun ◽  
May Phyu Thein Maw
Keyword(s):  
Drug Absorption ◽  
Oral Delivery ◽  
The Body ◽  
Drug Metabolizing Enzymes ◽  
Dependent Manner ◽  
Drug Bioavailability ◽  
Concentration Dependent Manner ◽  
Metabolizing Enzymes ◽  
Calcein Am

The oral delivery is the most practical route to deliver drugs into the body, however drug-metabolizing enzymes and drug transporters can play important roles in modulating drug absorption. This study intended to find a natural bioenhancer for improving drug bioavailability. Two limonoids, including limonin deepoxy and nomilin, isolated from pomelo pulp were studied and the inhibition effects on human CYP3A4 and P-gp were investigated. Testosterone 6β-hydroxylation was performed in recombinant human CYP3A4 to discover the effects on CYP activity. Daunorubicin transport in Caco-2 and calcein-AM uptake in LLC-PK1 and LLC-GA5-COL300 were conducted to evaluate the effects on P-gp function. The results show that both limonin deepoxy and nomilin could inhibit CYP3A4 and only nomilin exhibited mechanism-based inhibition. Nomilin was able to inhibit human P-gp in the concentration-dependent manner. Taken together, nomilin demonstrated strong activities on both CYP3A4 and P-gp, indicating that nomilin could possibly be used as a bioavailability enhancer.

scholarly journals SAT-736 Dissecting the Relative Role of Estrogen and Androgen in Fibrosis, Skeletal Muscle Atrophy, and Inguinal Hernia Formation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hong Zhao ◽  
Matthew Joseph Taylor ◽  
Tanvi Potluri ◽  
Stacy Kujawa ◽  
John Coon V ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Inguinal Hernia ◽  
Mouse Model ◽  
Aromatase Inhibitor ◽  
Muscle Atrophy ◽  
Regulatory Region ◽  
Relative Role ◽  
Hernia Formation ◽  
Human Aromatase

Abstract Introduction: More than one in four men develop symptomatic inguinal hernia, and hernia repair is the most commonly performed general surgical procedure in the US. Despite its prevalence, the molecular mechanisms causing inguinal hernia remain unclear. Aromatase, the key enzyme for the conversion of testosterone (T) to estradiol (E2), is present in human but not mouse skeletal muscle tissue. We recently demonstrated that robustly increased local E2 levels in lower abdominal muscle (LAM) tissue and decreased circulating T levels were associated with fibrosis and myocyte atrophy in LAM tissue, leading to severe scrotal (inguinal) hernia formation in a humanized aromatase transgenic mouse model (Aromhum) with a high LAM human aromatase expression. To further determine the relative role of estrogen and androgen in the development of inguinal hernia, we generated a novel mild Aromhum mouse model with lower LAM aromatase expression compared with the severe model. Methods: Mild Aromhum mice were followed for 6 months to determine hernia incidence and measure hernia size (n=30). We treated mild Aromhum mice with the aromatase inhibitor, letrozole (n=12) for 12 weeks. Circulating and LAM E2 levels in mice were measured using mass spectrometry. LAM tissue fibrosis and myocyte size were determined by Masson’s trichrome staining and H&E staining, respectively. Results: The mild Aromhum mice contain a single copy of the human aromatase genomic fragment with a truncated regulatory region, giving rise to significant but mildly elevated LAM E2 levels (2.5-fold) at 15 weeks of age. Interestingly, these mice maintain normal circulating T levels. Furthermore, we show that mildly increased LAM E2 without decreased circulating T levels cause hernia formation in about 88% of mild Aromhum mice in contrast to 100% hernia formation in mice containing the full-length human aromatase regulatory region (severe Aromhum model), suggesting that higher LAM estrogen and low serum T levels contribute to this severe phenotype. Treatment with an aromatase inhibitor restores LAM E2 levels to normal levels and completely prevents inguinal hernia formation in the mild Aromhum mice. In LAM fibroblasts of mild Aromhum mice, we find very high levels of estrogen receptor-α expression, which possibly mediates estrogen-induced hernia formation. Conclusion: Taken together, our findings from the mild Aromhum mouse model suggest that lower levels of estrogen excess in LAM are the primary driver of muscle atrophy and hernia formation because this mouse model do not exhibit circulating T deficiency. Our findings will constitute a starting point for dissecting the relative roles of estrogen and androgen action in inguinal hernia development. This has the potential to facilitate drug development to prevent and treat hernias, especially recurrent hernias after primary hernia repairs in vulnerable populations such as elderly men.

A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3580-3580
Author(s):  
J. F. Deeken ◽  
T. Cormier ◽  
D. K. Price ◽  
S. Steinberg ◽  
K. Tran ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase Ii ◽  
Drug Disposition ◽  
Individual Variability ◽  
Response To Therapy ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Pharmacogenetic Study ◽  
Metabolizing Enzymes ◽  
Genotyping Platform

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p<0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose.

scholarly journals Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

2011 ◽  
pp. 77-92
Author(s):  
Julie Scholler ◽  
Dominique Leveque
Keyword(s):  
Drug Interactions ◽  
Nuclear Receptors ◽  
Kinase Inhibitors ◽  
Drug Disposition ◽  
Clinical Impact ◽  
Published Data ◽  
Drug Metabolizing Enzymes ◽  
Orphan Nuclear Receptors ◽  
Metabolizing Enzymes ◽  
Molecular Determinants

This review presents the published data regarding the molecular determinants (drug metabolizing enzymes, drug transporters and orphan nuclear receptors) of approved anticancer kinase inhibitors pharmacokinetics in humans. The clinical impact of these determinants (drug disposition and drug–drug interactions) is also discussed.

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