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Lavé, Th.; Dupin, S.; Schmitt, Christophe; Vallès, B.; Ubeaud, G.; Chou, Ruby C.; Jaeck, Daniel; Coassolo, Philippe

doi:10.1023/a:1012036324237

Cited by 98 publications

(17 citation statements)

References 20 publications

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“…This is accomplished by a series of Phase I and Phase II metabolic reactions [5,44,45], mediated by a number of enzymes including the CYP450's, flavin containing mono-oxygenases (FMO), monoamine oxidase, peroxidases (Phase I enzymes) and glutathione-S-Transferase (GST), sulfotransferases (ST), Nacetyle transferases (NAT), UDP-glycosyltransferases (UDPGT), various methyl transferases (Phase II enzymes). In addition, NCE's are classified as low, intermediate or high extraction compounds, on the basis of clearance rates obtained from in vitro hepatic enzyme kinetic data [46][47][48][49]. The role of Phase I and Phase II enzymes in drug metabolism and the role of in vitro models in identifying them has been extensively reviewed in literature [5,43,44].…”

Section: Review Of In Vitro Models Of Primary Hepatocytes In Drug Dismentioning

confidence: 99%

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

Sivaraman

Leach

Townsend

et al. 2005

CDM

285

230

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In vitro models of the liver using isolated primary hepatocytes have been used as screens for measuring the metabolism, toxicity and efficacy of xenobiotics, for studying hepatocyte proliferation, and as bioartificial liver support systems. Yet, primary isolated hepatocytes rapidly lose liver specific functions when maintained under standard in vitro cell culture conditions. Many modifications to conventional culture methods have been developed to foster retention of hepatocyte function. Still, not all of the important functions -- especially the biotransformation functions of the liver -- can as yet be replicated at desired levels, prompting continued development of new culture systems. In the first part of this article, we review primary hepatocyte in vitro systems used in metabolism and enzyme induction studies. We then describe a scalable microreactor system that fosters development of 3D-perfused micro-tissue units and show that primary rat cells cultured in this system are substantially closer to native liver compared to cells cultured by other in vitro methods, as assessed by a broad spectrum of gene expression, protein expression and biochemical activity metrics. These results provide a foundation for extension of this culture model to other applications in drug discovery -- as a model to study drug-drug interactions, as a model for the assessment of acute and chronic liver toxicity arising from exposure to drugs or environmental agents; and as a disease model for the study of viral hepatitis infection and cancer metastasis.

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Section: Review Of In Vitro Models Of Primary Hepatocytes In Drug Dismentioning

confidence: 99%

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

Sivaraman

Leach

Townsend

et al. 2005

CDM

285

230

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show abstract

“…In order to overcome the need for mathematically factoring in binding terms some groups have advocated the inclusion of serum or albumin in in vitro incubations [35,36]. When the data presented in these publications are examined, it appears that the in vitro CL int can be scaled to the in vivo clearance directly by incorporating only blood flow.…”

Section: Prediction Of Hepatic Metabolic Clearancementioning

confidence: 99%

The Impact of In Vitro Binding on In Vitro - In Vivo Extrapolations, Projections of Metabolic Clearance and Clinical Drug-Drug Interactions

Grime¹,

Riley²

2006

CDM

111

112

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This review provides a vista of the current opportunities and remaining challenges in the area of in vitro-in vivo extrapolation, with particular emphasis on drug binding terms in predictive models, which has been the source of much controversy. Although the importance of fu(inc) (fraction unbound in in vitro incubations) has been acknowledged for decades, it is not always applied in practice. This is somewhat disappointing, since although it may be onerous to measure this term for large numbers of compounds, algorithms to estimate the term from logD(7.4) or logP have been detailed in the literature. These are sufficiently robust to negate routine measurement in early drug discovery. Several groups have recently established convincing relationships between unbound in vivo and in vitro metabolic intrinsic clearance (CL(int)). In the authors' laboratory, correlations of this type have been constructed for rat, dog and Man. The use and interpretation of these models within a drug discovery setting is discussed. The quantitative prediction of drug-drug interactions from in vitro cytochrome P450 (CYP) inhibition data remains a challenge. Although extensive literature databases are at last emerging, apparent ad hoc use of terms for in vivo inhibitor concentrations and only occasional consideration of fu(inc) may only have confused matters. The effect of accounting for drug binding on the accuracy of predictions is reviewed. Other themes including the impact of fu(inc) on relative activity factors (RAFs) and how in vitro data quality and inter-laboratory differences can confound quantitative human pharmacokinetic predictions are also developed.

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“…Several in vitro models have been developed to study drug metabolism, which include hepatocytes (18), liver microsomes (19) and recombinant CYP enzymes (20). Among them, liver microsomes have been the most common in-vitro model because of convenience, good reproducibility and high throughput.…”

Section: Discussionmentioning

confidence: 99%

Metabolic assessment in liver microsomes by co-activating cytochrome P450s and UDP-glycosyltransferases

Yan¹,

Caldwell²

2003

Eur. J. Drug Metab. Pharmacokinet.

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A "dual-activity" microsomal system in which both CYPs and UGTs were active was evaluated for studies of metabolic stability and in-vitro metabolite profiling. In this "dual-activity" system, alamethicin, a pore-forming peptide, was used to activate UGTs in human liver microsomes without affecting CYP activity. Interference studies indicated that CYP cofactors had little effect on UGT surrogate activity as measured by glucuronidation of acetaminophen and trifluoperazine. Further, UGT cofactor, UDPGA (< 2 mM), did not inhibit the marker activity of five major CYPs including 1A2, 2C9, 2C19, 2D6 and 3A4, suggesting that both oxidation and glucuronidation can be co-activated in microsomes. In a comparison study, compounds with significant glucuronidation showed distinct stability profiles in the "dual-activity" system, compared to the conventional microsomal incubation in which only CYPs were active. For compounds with minor or no glucuronidation, the metabolic stability remained similar between the "dual-activity" system and the conventional microsomal incubation. The feasibility of this "dual-activity" system utilized for metabolite profiling was also investigated using tramadol as a model drug. It was found that oxidative metabolites of tramadol generated in the "dual-activity" system matched those detected in the conventional microsomal incubation. However, tramadol glucuronide was observed in the "dual-activity" system but not in the conventional micromosal incubation. Results clearly suggest that the "dual-activity" system is a valuable in vitro model for metabolism studies in drug discovery.

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Abstract: The present approach, validated so far with 19 test compounds, appears to be a valuable tool to screen for compounds with respect to liver first-pass metabolism at an early phase of drug discovery.

Cited by 98 publications

References 20 publications

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

A Microscale In Vitro Physiological Model of the Liver: Predictive Screens for Drug Metabolism and Enzyme Induction

The Impact of In Vitro Binding on In Vitro - In Vivo Extrapolations, Projections of Metabolic Clearance and Clinical Drug-Drug Interactions

Metabolic assessment in liver microsomes by co-activating cytochrome P450s and UDP-glycosyltransferases

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