High Cell Permeability Does Not Predict Oral Bioavailability for Analogues of Cyclic Heptapeptide Sanguinamide A

2020 ◽  
Vol 73 (4) ◽  
pp. 344 ◽  
Author(s):  
Daniel S. Nielsen ◽  
Rink-Jan Lohman ◽  
Huy N. Hoang ◽  
David P. Fairlie ◽  
Timothy A. Hill
Keyword(s):  
Amino Acids ◽  
Membrane Permeability ◽  
Oral Bioavailability ◽  
Liver Microsomes ◽  
Cell Permeability ◽  
Rat Liver Microsomes ◽  
High Cell ◽  
Limited Data ◽  
Pharmacokinetic Properties ◽  
Cyclic Heptapeptide

The cyclic heptapeptide derivative, sanguinamide A, is a model scaffold for studying how component amino acids, heterocycles, and N-methylation influence membrane permeability and oral bioavailability. Membrane permeable sanguinamide A analogues have been reported, but there is limited data on their pharmacokinetic properties invivo. Here we report pharmacokinetic properties for highly cell and membrane permeable sanguinamide A analogues in rats and find that there is no correlation between reported permeability invitro and oral bioavailability invivo. We show that N-methylation of sanguinamide A analogues gives compounds with greater flexibility, greater susceptibility to degradation by rat liver microsomes, and lower oral bioavailability in rats.

The Effect of Dietary Sulfur-Containing Amino Acids on the Activity of Drug-Metabolizing Enzymes in Rat-Liver Microsomes

1979 ◽  
Vol 109 (5) ◽  
pp. 864-871 ◽  
Author(s):  
Jacques Magdalou ◽  
Daniele Steimetz ◽  
Anne-Marie Batt ◽  
Bernard Poullain ◽  
Gérard Siest ◽  
...  
Keyword(s):  
Amino Acids ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Drug Metabolizing Enzymes ◽  
Rat Liver Microsomes ◽  
Metabolizing Enzymes ◽  
Sulfur Containing

scholarly journals Effect of GTP on the dolichol pathway for protein glycosylation in rat liver microsomes

1993 ◽  
Vol 296 (3) ◽  
pp. 633-637 ◽  
Author(s):  
X Bossuyt ◽  
N Blanckaert
Keyword(s):  
Membrane Permeability ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Protein Glycosylation ◽  
Rat Liver Microsomes ◽  
Alpha Toxin ◽  
Gtp Hydrolysis ◽  
Dolichol Pathway ◽  
Previous Proposal ◽  
Stimulation Of

Incubation of native rat liver microsomes with GTP resulted in enhanced incorporation of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc into lipid acceptors. The stimulation of GlcNAc transfer by GTP was specific for GTP; ATP exerted no effect. The GTP effect was blocked by a non-hydrolysable GTP analogue guanosine 5′-[beta gamma-imido]triphosphate, indicating that GTP hydrolysis was crucial. Though dolichyl pyrophosphate NN′-diacetylchitobiose [Dol-PP-(GlcNAc)2] was the main radiolabelled product formed upon incubation of GTP-treated microsomes with UDP-GlcNAc, GTP selectively stimulated UDP-GlcNAc:dolichyl phosphate (Dol-P) N-acetylglucosaminyl 1-phosphotransferase (N-acetylglucosaminyl 1-phosphotransferase). This conclusion was reached on the basis of experiments in which tunicamycin was used to selectively inhibit N-acetylglucosaminyl 1-phosphotransferase. The enhanced transformation of Dol-P to dolichyl pyrophosphate N-acetylglucosamine (Dol-PP-GlcNAc) by GTP ultimately led to enhanced protein glycosylation. GTP-induced stimulation of GlcNAc incorporation in lipid and protein by GTP was observed also in microsomes fully permeabilized with Staph. aureus alpha-toxin. These findings refute the previous proposal [Godelaine, Beaufay, Wibo and Ravoet (1983) J. Cell Biol. 97, 340-350] that increased membrane permeability constitutes the mechanism whereby GTP activates the reactions of the dolichol pathway.

ALLOXAN DIABETES AND IN VITRO PROTEIN BIOSYNTHESIS IN RAT LIVER MICROSOMES AND MITOCHONDRIA

1960 ◽  
Vol 20 (3) ◽  
pp. 256-265 ◽  
Author(s):  
A. KORNER
Keyword(s):  
Amino Acids ◽  
Growth Hormone ◽  
Soluble Fraction ◽  
Protein Biosynthesis ◽  
Liver Microsomes ◽  
Diabetic Rats ◽  
Rat Liver Microsomes ◽  
Small Doses ◽  
Polypeptide Chains

SUMMARY 1. Mitochondria and microsomes isolated from livers of alloxan-diabetic rats incorporate less radioactive amino acid into their proteins in vitro than the corresponding subcellular particles prepared from livers of normal rats. 2. Most of the decrease in incorporation of amino acids shown by the microsome system prepared from alloxan-diabetic rats is caused by alterations in the ability of the microsomes to assemble amino acids into polypeptide chains, but some depressing effect on the ability of the soluble fraction of the liver cells to prepare acids for incorporation is also found in alloxan-diabetic rats. 3. Treatment of alloxan-diabetic rats with insulin restored towards normal the depressed ability of both mitochondria and microsomes to incorporate amino acids into protein in vitro. 4. Treatment of alloxan-diabetic rats with small doses of growth hormone increased the incorporation of amino acids into protein by mitochondria and microsomes in vitro, but treatment of the rats with larger doses of growth hormone resulted in further depression of the in vitro incorporating ability of both subcellular particles.

Metabolic Analysis of Triptolide Microspheres in Human, Dog, Rabbit and Rat Liver Microsomes with UPLC-MS/MS Method

2020 ◽  
Vol 17 ◽  
Author(s):  
LiJuan Wang ◽  
Yan Liu ◽  
Rui Li ◽  
DongXian He
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Liver Microsomes ◽  
Good Precision ◽  
Kinetics Parameters ◽  
Measure Concentration ◽  
Standard Curve ◽  
Variation Of Parameters

Objectives: Triptolide (TPL) has been shown to have a good clinical effect on rheumatoid arthritis (RA). We designed TPL microspheres (TPL-MS) and investigated its metabolic behavior in human, dog, rabbit and rat liver microsomes (HLM, DLM, RLM and SDRLM) with UPLC-MS/MS method. Methods: First, a UPLC-MS/MS method was established to measure concentration of TPL in samples. The sample was separated on a C18 column (2.1×100 mm, 1.8μm) and eluted with a gradient elution. The precursor ion/product ion were m/z 378.1/361.0 for TPL and 260.0/116.2 for the internal standard. Then T1/2, Vmax and CLint were calculated from the above data. Finally, the metabolites of TPL-MS were identified by high-resolution UPLC-MS/MS. The sample was separated on a C18 column (2.1×100 mm, 2.2 μm) and eluted with isocratic elution. Mass spectrometric detection was carried out on a thermo Q-exactive mass spectrometer with HESI. The scanning range of precursor ions was from m/z 50 to m/z 750. Result and Discussion: Through several indicators including standard curve, precision, accuracy, stability, matrix effect and recovery rate, the enzymatic kinetics parameters including T1/2, Vmax and CLint were completed. Several metabolites of TPL-MS were identified. Conclusion: UPLC-MS/MS method is an accurate and sensitive method for determination of TPL in liver microsome samples with good precision, accuracy and stability. The variation of parameters indicated that the microspheres can delay the elimination of TPL in liver microsomes. The metabolism of TPL-MS varied among species, but no new metabolites appeared.

scholarly journals Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 776
Author(s):  
Sin-Eun Kim ◽  
Seung-Bae Ji ◽  
Euihyeon Kim ◽  
Minseon Jeong ◽  
Jina Kim ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Human Liver ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Rat Liver Microsomes ◽  
High Resolution Mass ◽  
Resolution Mass

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

scholarly journals The metabolism of gelsevirine in human, pig, goat and rat liver microsomes

2021 ◽  
Author(s):  
Hua‐Hai Zhang ◽  
Wen‐Jia Yang ◽  
Ya‐Jun Huang ◽  
Wen‐Jing Li ◽  
Shuo‐Xin Zhang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes
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