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1.
Macromol Rapid Commun ; : e2400226, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38837553

ABSTRACT

Coordinative chain transfer polymerization (CCTP) of ethylene and its copolymerization with 1,3-butadiene is conducted in toluene at 80 °C using a combination of {(Me2Si(C13H8)2)Nd(µ-BH4)[(µ-BH4)Li(THF)]}2 (1) metal complex and various organomagnesium compounds used as chain transfer agents including n-butyl-n-octyl-magnesium (BOMAG), n-butyl-mesityl-magnesium (n-BuMgMes), n-butyl-magnesium chloride (n-BuMgCl), n-pentyl-magnesium bromide (n-C5H11MgBr), pentanediyl-1,5-di(magnesium bromide) (PDMB) and isobutyl-magnesium chloride (i-BuMgCl). Kinetics and performance in terms of control of the (co)polymerization are comparatively discussed particularly considering the presence of ether and the nature of the organomagnesium compounds employed. Taking advantage of the well-known reactivity between nitrile and molecular organomagnesium compounds, the functionalization of the chains is further carried out by deactivation of the polymerization medium with benzonitrile or methoxybenzonitrile compounds leading to ketone ω-functionalized chains. The success of the functionalizations is extended to coupling strategies using dinitrile reagents and to the functionalization of high molar mass ethylene butadiene rubber (EBR).

2.
Angew Chem Int Ed Engl ; 61(26): e202204249, 2022 Jun 27.
Article in English | MEDLINE | ID: mdl-35403806

ABSTRACT

Anionic polymerization of butadiene or/and styrene is performed with lithium initiators, functional or not. The polymer chains are subsequently transferred to magnesium. The resulting polymeryl-magnesium compounds were combined with {(Me2 Si(C13 H8 )2 )Nd(µ-BH4 )[(µ-BH4 )Li(THF)]}2 metallocene complex to act as macromolecular chain transfer agents (macroCTAs) in coordinative chain transfer polymerization (CCTP) of ethylene (E) or its copolymerization (CCTcoP) with butadiene (B). Block copolymers were produced for the first time by this switch from anionic polymerization to CCTP. Hard and soft blocks such as PB, polystyrene (PS), poly(styrene-co-butadiene) (SBR) obtained by anionic polymerization and PE or poly(ethylene-co-butadiene) (EBR) produced by CCT(co)P were combined and the corresponding structures were characterized.

3.
Drug Metab Dispos ; 44(1): 50-60, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26467767

ABSTRACT

Prediction of drug-drug interactions due to cytochrome P450 isoform 3A4 (CYP3A4) overexpression is important because this CYP isoform is involved in the metabolism of about 30% of clinically used drugs from almost all therapeutic categories. Therefore, it is mandatory to attempt to predict the potential of a new compound to induce CYP3A4. Among several in vitro-in vivo extrapolation methods recently proposed in the literature, an approach using a scaling factor, called a d factor, for a given hepatocyte batch to provide extrapolation between in vitro induction data and clinical outcome has been adopted by leading health authorities. We challenged the relevance of the calibration factor determined using a set of 15 well-known clinical CYP3A4 inducers or the potent CYP3A4 inducer rifampicin only. These investigations were conducted using six batches of human hepatocytes and an established HepaRG cell line. Our findings show that use of a calibration factor is preferable for clinical predictions, as shown previously by other investigators. Moreover, the present results also suggest that the accuracy of prediction through calculation of this factor is sufficient when rifampicin is considered alone, and the use of a larger set of fully characterized CYP3A4 clinical inducers is not required. For the established HepaRG cell line, the findings obtained in three experiments using a single batch of cells show a good prediction accuracy with or without the d factor. Additional investigations with different batches of HepaRG cell lines are needed to confirm these results.


Subject(s)
Cryopreservation , Cytochrome P-450 CYP3A Inducers/pharmacology , Cytochrome P-450 CYP3A/biosynthesis , Drug Interactions , Hepatocytes/drug effects , Hepatocytes/enzymology , Adult , Aged , Cell Line , Cell Shape/drug effects , Cell Survival/drug effects , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A Inducers/toxicity , Dose-Response Relationship, Drug , Enzyme Induction , Female , Humans , Male , Middle Aged , Models, Biological , RNA, Messenger/biosynthesis , Rifampin/pharmacology
4.
Xenobiotica ; 45(1): 29-44, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25068923

ABSTRACT

1. The quantitative prediction of the pharmacokinetic parameters of a drug from data obtained using human in vitro systems remains a significant challenge i.e. prediction of metabolic clearance in humans and estimation of the relative contribution of enzymes involved in the clearance. This has become particularly problematic for low turnover compounds. 2. Having human hepatocytes with stable cellular function over several days that adequately mimic the complexity of the physiological environment would be a major advance. Thus, we evaluated human hepatocytes, maintained in culture during 7 days in the microfluidic LiverChip™ system, in terms of morphological appearance, relative mRNA expression of phase I and II enzymes and transporters as a function of time, and metabolic capacity using probe substrates. 3. The results showed that mRNA levels of the major genes for enzymes involved in drug metabolism were well-maintained over a 7-day period of culture. Furthermore, after 4 days of culture, in the Liverchip™ device, human hepatocytes exhibited higher or similar CYPs activities compared to 1 day of culture in 2D-static conditions. 4. The functional data were supported by light/electron microscopies and immunohistochemistry showing viable tissue structure and well-differentiated human hepatocytes: presence of cell junctions, glycogen storage, and bile canaliculi.


Subject(s)
Cell Culture Techniques/instrumentation , Cryopreservation , Cytochrome P-450 Enzyme System/metabolism , Hepatocytes/metabolism , Perfusion/instrumentation , Cells, Cultured , Hepatocytes/ultrastructure , Metabolic Detoxication, Phase II , Receptors, Cytoplasmic and Nuclear/metabolism
5.
Pharmacol Res Perspect ; 2(3): e00044, 2014 Jun.
Article in English | MEDLINE | ID: mdl-25505590

ABSTRACT

The in vitro metabolism of dronedarone and its major metabolites has been studied in human liver microsomes and cryopreserved hepatocytes in primary culture through the use of specific or total cytochrome P450 (CYP) and monoamine oxidase (MAO) inhibitors. The identification of the main metabolites and enzymes participating in their metabolism was also elucidated by using rhCYP, rhMAO, flavin monooxygenases (rhFMO) and UDP-glucuronosyltransferases (rhUGT) and liquid chromatography/tandem mass spectrometry (LC/MS-MS) analysis. Dronedarone was extensively metabolized in human hepatocytes with a metabolic clearance being almost completely inhibited (98 ± 2%) by 1-aminobenzotriazole. Ketoconazole also inhibited dronedarone metabolism by 89 ± 7%, demonstrating the crucial role of CYP3A in its metabolism. CYP3A isoforms mostly contributed to N-debutylation while hydroxylation on the butyl-benzofuran moiety was catalyzed by CYP2D6. However, hydroxylation on the dibutylamine moiety did not appear to be CYP-dependent. N-debutyl-dronedarone was less rapidly metabolized than dronedarone, the major metabolic pathway being catalyzed by MAO-A to form propanoic acid-dronedarone and phenol-dronedarone. Propanoic acid-dronedarone was metabolized at a similar rate to that of N-debutyl-dronedarone and was predominantly hydroxylated by CYP2C8 and CYP1A1. Phenol-dronedarone was extensively glucuronidated while C-dealkyl-dronedarone was metabolized at a slow rate. The evaluation of the systemic clearance of each metabolic process together with the identification of both the major metabolites and predominant enzyme systems and isoforms involved in the formation and subsequent metabolism of these metabolites has enhanced the overall understanding of metabolism of dronedarone in humans.

6.
Drug Metab Dispos ; 36(5): 851-62, 2008 May.
Article in English | MEDLINE | ID: mdl-18256203

ABSTRACT

Midazolam (MDZ) is one of the most commonly used in vivo and in vitro CYP3A4 probe substrates for drug-drug interactions (DDI) studies. The major metabolic pathway of MDZ in humans consists of the CYP3A4-mediated 1'-hydroxylation followed by urinary excretion as 1'-O-glucuronide derivative. In the present study, following incubation of MDZ with human liver microsomes supplemented with UDP-glucuronic acid, two major high-performance liquid chromatography (HPLC) peaks were isolated. HPLC and liquid chromatography/tandem mass spectrometry analyses identified these two metabolites as quaternary direct N-glucuronides of MDZ, thus revealing an additional metabolic pathway for MDZ. (1)H NMR spectrometry studies were performed showing that these two glucuronides were beta-N-glucuronides, which could be considered as two different conformers of the same molecule. According to molecular modeling experiments, the two glucuronide derivatives could be involved in atropoisomerism equilibrium. The formation of MDZ N-glucuronide exhibited moderate intersubject variability (at most 4.5-fold difference, n = 10). Among the recombinant human UDP glucuronosyltransferase (UGT) isoforms tested, only isoform UGT1A4 catalyzed the N-glucuronidation of MDZ fitting a Michaelis-Menten model. K(m) and V(max) values were 29.9 +/- 2.4 microM and 659.6 +/- 19.0 pmol/min/mg protein, respectively. The N-glucuronide derivative was found in human hepatocytes incubated under control conditions but also in the presence of the well known CYP3A4 inhibitor, ketoconazole. In the context of the in vitro study of CYP3A4-mediated DDI using MDZ and ketoconazole, direct MDZ N-glucuronidation may partly compensate the decrease in MDZ metabolic clearance caused by the addition of the inhibitor, thus potentially leading to underestimation, at least in vitro, of the extent of DDI.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Glucuronides/metabolism , Glucuronosyltransferase/metabolism , Hepatocytes/metabolism , Microsomes, Liver/metabolism , Midazolam/metabolism , Adolescent , Adult , Aged , Cells, Cultured , Cytochrome P-450 CYP3A Inhibitors , Drug Interactions , Female , Humans , Ketoconazole/metabolism , Male , Middle Aged
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