scholarly journals PREDICTION OF THE IN VIVO DRUG METABOLIZING ACTIVITY IN HUMAN LIVER FROM IN VITRO DATA ON METABOLISM : THE USE OF HUMAN LIVER MICROSOMES AND RECOMBINANT HUMAN CYP ISOZYMES

1999 ◽  
Vol 14 (supplement) ◽  
pp. 92-93
Author(s):  
Yukiko NAKAJIMA ◽  
Kiyomi ITO ◽  
Yoshihiiko FUNAE ◽  
Susumu IMAOKA ◽  
Noriaki SHIMADA ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Vitro Data ◽  
In Vitro Data ◽  
Cyp Isozymes

scholarly journals Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Hye Young Ji ◽  
Kwang Hyeon Liu ◽  
Ji Hyeon Jeong ◽  
Dae-Young Lee ◽  
Hyun Joo Shim ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Udp Glucuronosyltransferase ◽  
Index Value ◽  
Tuber Extract ◽  
Corydalis Tuber

DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC50) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol1′-hydroxylation with an inhibition constant (Ki) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol1′-hydroxylation, with aKivalue of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC50equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate thein vivoextent of the observedin vitrointeractions.

Presence of enniatin B and its hepatic metabolites in plasma and liver samples from broilers and eggs from laying hens

2014 ◽  
Vol 7 (2) ◽  
pp. 167-175 ◽  
Author(s):  
L. Ivanova ◽  
C.K. Fæste ◽  
E. Van Pamel ◽  
E. Daeseleire ◽  
A. Callebaut ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
Serum Samples ◽  
Cytotoxic Effects ◽  
Spectrometric Data ◽  
Metabolite Profiles ◽  
Vitro Data ◽  
In Vitro Data ◽  
Animal Consumption

Enniatins, a large group of cyclodepsipeptides, are widely distributed contaminants of different crops intended for human and animal consumption. Enniatin B is one of the principal analogues in species of the genus Fusarium, known to have ionophoric, antibiotic, and insecticidal activity. Regardless of considerable cytotoxic effects observed in vitro, enniatins have been characterised as compounds with low acute toxicity in vivo. The biotransformation of enniatin B has previously been elucidated in liver microsomes, and 12 different metabolites (M1 to M12) have been reported. In order to provide a better basis for understanding the potential toxic effects in humans and animals, different samples (eggs, livers, plasma) from two different feeding studies have been analysed for the presence of enniatin B and its hepatic metabolites. The earlier reported metabolite M11, and a novel metabolite (designated M13), were dominant in liver samples from enniatin B exposed broilers. The peak area corresponding to the sodiated molecular ion of M11 was approximately 2.5 times larger than that of parent enniatin B in liver samples collected after one week of exposure. The same metabolites were also present in serum samples. In egg samples, only metabolites M13 and M4 were detected. The comparison of mass spectrometric data of M13 and enniatin B suggested that M13 is a monohydroxylated metabolite. The hepatic biotransformation of enniatin B was also investigated in vitro in chicken microsomes demonstrating good correlation with the metabolite profiles in the chicken samples. The results of the present study demonstrated an extensive biotransformation of enniatin B in vivo confirming previously reported in vitro data.

scholarly journals An in vitro toolbox to accelerate anti-malarial drug discovery and development

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Susan A. Charman ◽  
Alice Andreu ◽  
Helena Barker ◽  
Scott Blundell ◽  
Anna Campbell ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Target Product ◽  
Experimental Conditions ◽  
Data Set ◽  
Vitro Data ◽  
In Vitro Data

Abstract Background Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. Methods Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS. Results Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. Conclusions This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

Rapid identification of MDMB-CHMINACA metabolites using Zebrafish and Human Liver microsomes as the Biotransformation system by LC-QE-HF-MS

2020 ◽  
Author(s):  
Duo-qi Xu ◽  
Yong Dai ◽  
Wen-fang Zhang ◽  
Ji-fen Wang ◽  
Yan-yan Wang ◽  
...  
Keyword(s):  
Animal Model ◽  
Human Liver ◽  
Mass Measurement ◽  
Liver Microsomes ◽  
Rapid Identification ◽  
Human Liver Microsomes ◽  
Designer Drugs ◽  
Published Data

Abstract MDMB-CHMINACA is a newly synthetic cannabinoid which scoped in NMS Lab, USA. Since there are currently no published data on MDMB-CHMINACA metabolism, we aimed to identify its biotransformation pathways and major metabolites. Liquid chromatography Q-Extractive HF Hybrid Quadrupole-Orbitrap mass spectrometry (LC-QE-HF-MS) using full scan positive ion mode and targeted MS/MS (ddms2) techniques with accurate mass measurement were employed to analyze the metabolic sites and pathways. An in vivo metabolic animal model of zebrafish was established to verify the metabolic pathways of MDMB-CHMINACA obtained from human liver microsomal experiment in vitro. The results showed that 29 metabolites were generated in the zebrafish animal model and human liver microsomes model. Biotransformations mainly occurred at the cyclohexylmethyl tail of the compound, minor reactions also occurred at the tert-butyl chain, and no reaction was analysised at the indazole ring. We recommend M1 group (MDMB-CHMINACA ester hydroxylation), and M2 group (MDMB-CHMINACA monohydroxylation) as the potential poisoning markers to document MDMB-CHMINACA intake in clinical and forensic cases. Additionally, this study provides preliminary information regarding the metabolism of MDMB-CHMINACA that will guide analytical standard manufacturers to better provide suitable references for further studies on newly encountered designer drugs.

Herb-Drug Interaction of 50 Chinese Herbal Medicines on CYP3A4 Activity in Vitro and in Vivo

2012 ◽  
Vol 40 (01) ◽  
pp. 57-73 ◽  
Author(s):  
Li-Heng Pao ◽  
Oliver Yoa-Pu Hu ◽  
Hsien-Yuan Fan ◽  
Chang-Ching Lin ◽  
Liang-Chun Liu ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Drug Interactions ◽  
Human Liver ◽  
Liver Microsomes ◽  
Herbal Medicines ◽  
Human Liver Microsomes ◽  
Chinese Herbal Medicines ◽  
Chinese Herbal

The purpose of this study is to evaluate the effects of Chinese herbal medicines on the enzymatic activity of CYP3A4 and the possible metabolism-based herb-drug interactions in human liver microsomes and in rats. Fifty single-herbal preparations were screened for the activity of CYP3A4 using human liver microsomes for an in vitro probe reaction study. The enzymatic activity of CYP3A4 was estimated by determing the 6β-hydroxytestosterone metabolized from testosterone performed on a liquid chromatography-tandem mass spectrometry (LC-MS/MS). Huang Qin (Scutellaria baicalensis Geprgi), Mu Dan Pi (Paeonia suffruticosa Andr.), Ji Shiee Terng (Spatholobus suberectus Dunn.) and Huang Qi (Astragalus membranaceus [Fisch] Bge) have been demonstrated to have remarkable inhibiting effects on the metabolism of CYP3A4, whereas Xi Yi Hua (Magnolia biondii Pamp.) exhibited a moderate inhibition. These five single herbs were further investigated in an animal study using midazolam. Mu Dan Pi, Ji Shiee Terng and Huang Qi were observed to have greatly increased in the C max and AUC of midazolam. This study provides evidence of possible herb-drug interactions involved with certain single herbs.

Sign in / Sign up

Export Citation Format

Share Document