Utility of In Vitro Systems and Preclinical Data for the Prediction of Human Intestinal First-Pass Metabolism during Drug Discovery and Preclinical Development

Karlsson, Fredrik; Bouchène, Salim; Hilgendorf, Constanze; Dolgos, Hugues; Peters, Sheila Annie

doi:10.1124/dmd.113.051664

Cited by 39 publications

(36 citation statements)

References 57 publications

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“…Erythromycin is reported to be mostly metabolized by CYP3A (Karlsson et al, 2013), consistent with the high CYP3A f m value observed in this study (Table 2). Tizanidine is a CYP1A2 substrate with reported inhibition of 85% by furafylline (Granfors et al, 2004), which is in line with our measured value of 83%.…”

Section: Discussionsupporting

confidence: 80%

Novel Cytochrome P450 Reaction Phenotyping for Low-Clearance Compounds Using the Hepatocyte Relay Method

Yang

Atkinson

2015

Drug Metabolism and Disposition

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A novel cytochrome P450 (P450) reaction phenotyping method for low-clearance compounds has been developed for eight P450 enzymes (CYP1A2, 2B6, 2D6, 2C8, 2C9, 2C19, 3A, and 3A4) and pan-cytochrome using the hepatocyte relay approach. Selective mechanism-based inhibitors were used to inactivate the individual P450 enzymes during preincubation, and inactivators were removed from the incubation before adding substrates to minimize reversible inhibition and maximize inhibitor specificity. The inhibitors were quite selective for specific P450 isoforms using the following inhibitor concentrations and preincubation times: furafylline (1 mM, 15 minutes) for CYP1A2, phencyclidine (20 mM, 15 minutes) for 2B6, paroxetine (1.8 mM, 15 minutes) for CYP2D6, gemfibrozil glucuronide (100 mM, 30 minutes) for 2C8, tienilic acid (15 mM, 30 minutes) for 2C9, esomeprazole (8 mM, 15 minutes) for 2C19, troleandomycin (25 mM, 15 minutes) for 3A4/5, CYP3cide (2 mM, 15 minutes) for 3A4, and 1-aminobenzotriazole (1 mM, 30 minutes) supplemented with tienilic acid (15 mM, 30 minutes) for pan-cytochrome. The inhibitors were successfully applied to the hepatocyte relay method in a 48-well format for P450 reaction phenotyping of low-clearance compounds. This novel method provides a new approach for determining the fraction metabolized of low-turnover compounds that are otherwise challenging with the traditional methods, such as chemical inhibitors with human liver microsomes and hepatocytes or human recombinant P450 enzymes.

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Section: Discussionsupporting

confidence: 80%

Novel Cytochrome P450 Reaction Phenotyping for Low-Clearance Compounds Using the Hepatocyte Relay Method

Yang

Atkinson

2015

Drug Metabolism and Disposition

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“…Although it is reasonable to assume that the free liver concentration could be similar to the free plasma concentration when a perfusion-limited model is used, the use of this assumption to determine the metabolite concentration at interacting sites is still uncertain, especially for a highly lipophilic metabolite such as MDEA. Other parameters, such as free inhibitory metabolite concentration in the gut (Yang et al, 2007;Karlsson et al, 2013) and in vivo inhibition potency of the inhibitory metabolite, can also affect the prediction. A good understanding of the source of uncertainty for these parameters and its impact on the prediction is important.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions Involving Inhibitory Metabolite: A Case Study of Amiodarone

Chen¹,

Mao²,

Hop³

2014

Drug Metab Dispos

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Evaluation of drug-drug interaction (DDI) involving circulating inhibitory metabolites of perpetrator drugs has recently drawn more attention from regulatory agencies and pharmaceutical companies. Here, using amiodarone (AMIO) as an example, we demonstrate the use of physiologically based pharmacokinetic (PBPK) modeling to assess how a potential inhibitory metabolite can contribute to clinically significant DDIs. Amiodarone was reported to increase the exposure of simvastatin, dextromethorphan, and warfarin by 1.2-to 2-fold, which was not expected based on its weak inhibition observed in vitro. The major circulating metabolite, mono-desethyl-amiodarone (MDEA), was later identified to have a more potent inhibitory effect. Using a combined "bottom-up" and "top-down" approach, a PBPK model was built to successfully simulate the pharmacokinetic profile of AMIO and MDEA, particularly their accumulation in plasma and liver after a long-term treatment. The clinical AMIO DDIs were predicted using the verified PBPK model with incorporation of cytochrome P450 inhibition from both AMIO and MDEA. The closest prediction was obtained for CYP3A (simvastatin) DDI when the competitive inhibition from both AMIO and MDEA was considered, for CYP2D6 (dextromethorphan) DDI when the competitive inhibition from AMIO and the competitive plus time-dependent inhibition from MDEA were incorporated, and for CYP2C9 (warfarin) DDI when the competitive plus time-dependent inhibition from AMIO and the competitive inhibition from MDEA were considered. The PBPK model with the ability to simulate DDI by considering dynamic change and accumulation of inhibitor (parent and metabolite) concentration in plasma and liver provides advantages in understanding the possible mechanism of clinical DDIs involving inhibitory metabolites.

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“…Though not often accounted for, the fraction that escapes luminal degradation, by, e.g., digestive enzymes or conversion by the intestinal microbiota, also affects the oral bioavailability. This fraction is generally assumed to be part of f gut , as an additional source of gut metabolism (Karlsson et al, 2013).…”

Section: In Vivo Methods For Kinetics Predictive Value For Humans Amentioning

confidence: 99%

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

Punt

2017

ALTEX

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Utility of In Vitro Systems and Preclinical Data for the Prediction of Human Intestinal First-Pass Metabolism during Drug Discovery and Preclinical Development

Cited by 39 publications

References 57 publications

Novel Cytochrome P450 Reaction Phenotyping for Low-Clearance Compounds Using the Hepatocyte Relay Method

Novel Cytochrome P450 Reaction Phenotyping for Low-Clearance Compounds Using the Hepatocyte Relay Method

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions Involving Inhibitory Metabolite: A Case Study of Amiodarone

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

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