Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes

Glaeser, Hartmut; Drescher, Siegfried; Eichelbaum, Michel; Fromm, MF

doi:10.1111/j.1365-2125.2004.02265.x

Cited by 80 publications

(65 citation statements)

References 43 publications

(66 reference statements)

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“…Rifampin in vivo E max optimized from intravenous data is based solely on hepatic induction, and improvement in prediction success for oral DDIs can be expected only if induction effect is the same in intestine and liver. Data on rifampin induction of CYP3A4 mRNA and protein in enterocytes are limited and based on a small group of healthy subjects, with no corresponding matched hepatic induction data (Glaeser et al, 2005). However, this study indicated differential and lower intestinal response to rifampin relative to liver.…”

Section: Downloaded Frommentioning

confidence: 85%

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

Templeton¹,

Houston²,

Galetin³

2011

Drug Metab Dispos

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ABSTRACT:Rifampin is a potent inducer of CYP3A4 in vitro and precipitates numerous drug-drug interactions (DDIs) when coadministered with CYP3A4 substrates. In the current study, we have critically assessed reported rifampin in vitro CYP3A4 induction data in Fa2N-4, HepaRG, and cryopreserved or primary human hepatocytes, using either CYP3A4 mRNA or probe substrate metabolism as induction endpoints. An in vivo data base of intravenously administered victim drugs (assuming hepatic induction only) was collated (n ‫؍‬ 18) to assess the predictive utility of these in vitro systems and to optimize rifampin in vivo E max . In addition, the effect of substrate hepatic extraction ratio on prediction accuracy was investigated using prediction boundaries proposed recently (Drug Metab Dispos 39:170-173). Incorporation of hepatic extraction ratio in the prediction model resulted in accurate prediction of 89% of intravenous induction DDIs (n ‫؍‬ 18), regardless of the in vitro system or induction endpoint (mRNA or CYP3A4 activity). Effects of in vitro parameters from different cellular systems, and optimized in vivo E max , on the prediction of 21 oral DDIs were assessed. Use of mRNA data resulted in pronounced overprediction across all systems, with 86 to 100% of DDIs outside the acceptable prediction limits; in contrast, CYP3A4 activity predicted up to 62% of the oral DDIs within limits. Although prediction accuracy of oral DDIs was improved when using intravenous optimized rifampin E max , >35% of DDIs were incorrectly assigned, suggesting potential differential E max between intestine and liver. Implications of the findings and recommendations for prediction of rifampin DDIs are discussed.

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Section: Downloaded Frommentioning

confidence: 85%

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

Templeton¹,

Houston²,

Galetin³

2011

Drug Metab Dispos

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“…Nevertheless, we postulate that CYP2C8 induction only has a minimal effect on repaglinide pharmacokinetics, because (i) repaglinide systemic clearance is majorly determined by the hepatic uptake clearance and an increase in hepatic metabolic activity is less likely to affect the systemic clearance (Table 2), and (ii) as noted with the simulations here, increase in the gut metabolism is the major driver for observed decrease in repaglinide exposure (particularly when rifampicin and repaglinide doses were separated by .12 hours), and CYP2C8 contribution to the gut metabolism is believed to be relatively low (Paine et al, 2006). Nevertheless, although no clinical evidence exist, expression and in vitro data suggest that rifampicin significantly induces the intestinal CYP2C8 and CYP2C9 isoforms and may partially contribute to such interactions (Lapple et al, 2003;Glaeser et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Prediction of Repaglinide-Rifampicin Complex Drug Interactions Using Dynamic and Static Mechanistic Models: Delineating Differential CYP3A4 Induction and OATP1B1 Inhibition Potential of Rifampicin

Varma

Lin

et al. 2013

Drug Metab Dispos

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Repaglinide is mainly metabolized by cytochrome P450 enzymes CYP2C8 and CYP3A4, and it is also a substrate to a hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study is to predict the dosing time-dependent pharmacokinetic interactions of repaglinide with rifampicin, using mechanistic models. In vitro hepatic transport of repaglinide, characterized using sandwich-cultured human hepatocytes, and intrinsic metabolic parameters were used to build a dynamic whole-body physiologically-based pharmacokinetic (PBPK) model. The PBPK model adequately described repaglinide plasma concentration-time profiles and successfully predicted area under the plasma concentration-time curve ratios of repaglinide (within 6 25% error), dosed (staggered 0-24 hours) after rifampicin treatment when primarily considering induction of CYP3A4 and reversible inhibition of OATP1B1 by rifampicin. Further, a static mechanistic "extended net-effect" model incorporating transport and metabolic disposition parameters of repaglinide and interaction potency of rifampicin was devised. Predictions based on the static model are similar to those observed in the clinic (average error ∼19%) and to those based on the PBPK model. Both the models suggested that the combined effect of increased gut extraction and decreased hepatic uptake caused minimal repaglinide systemic exposure change when repaglinide is dosed simultaneously or 1 hour after the rifampicin dose. On the other hand, isolated induction effect as a result of temporal separation of the two drugs translated to an approximate 5-fold reduction in repaglinide systemic exposure. In conclusion, both dynamic and static mechanistic models are instrumental in delineating the quantitative contribution of transport and metabolism in the dosing time-dependent repaglinide-rifampicin interactions.

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“…Hepatic CYP3A4 is induced by rifampicin and is regulated mainly by PXR (Drocourt et al, 2002). Intestinal CYP3A4 is induced by 1a,25-dihydroxyvitamin D 3 through vitamin D receptor and is also induced by rifampicin (Kolars et al, 1992;Glaeser et al, 2005;van de Kerkhof et al, 2008). In our differentiated enterocytes, not only CYP3A4 mRNA expression but also CYP3A4/5 activity were induced by 1a,25-dihydroxyvitamin D 3 (Fig.…”

Section: Differentiation Of Human Ips Cells To Enterocytes 607mentioning

confidence: 95%

Generation of Enterocyte-Like Cells with Pharmacokinetic Functions from Human Induced Pluripotent Stem Cells Using Small-Molecule Compounds

et al. 2015

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The small intestine plays an important role in all aspects of pharmacokinetics, but there is no system for the comprehensive evaluation of small-intestinal pharmacokinetics, including drug metabolism and absorption. In this study, we aimed to construct an intestinal pharmacokinetics evaluation system and to generate pharmacokinetically functional enterocytes from human induced pluripotent stem cells. Using activin A and fibroblast growth factor 2, we differentiated these stem cells into intestinal stem cell-like cells, and the resulting cells were differentiated into enterocytes in a medium containing epidermal growth factor and small-molecule compounds. The differentiated cells expressed intestinal marker genes and drug transporters. The expression of sucrase-isomaltase, an intestine-specific marker, was markedly increased by small-molecule compounds. The cells exhibited activities of drug-metabolizing enzymes expressed in enterocytes, including CYP1A1/2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT, and sulfotransferase. Fluorescence-labeled dipeptide uptake into the cells was observed and was inhibited by ibuprofen, an inhibitor of the intestinal oligopeptide transporter solute carrier 15A1/PEPT1. CYP3A4 mRNA expression level was increased by these compounds and induced by the addition of 1a,25-dihydroxyvitamin D 3 . CYP3A4/5 activity was also induced by 1a,25-dihydroxyvitamin D 3 in cells differentiated in the presence of the compounds. All these results show that we have generated enterocyte-like cells that have pharmacokinetic functions, and we have identified small-molecule compounds that are effective for promoting intestinal differentiation and the gain of pharmacokinetic functions. Our enterocyte-like cells would be useful material for developing a novel evaluation system to predict human intestinal pharmacokinetics.

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Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes

Cited by 80 publications

References 43 publications

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

Quantitative Prediction of Repaglinide-Rifampicin Complex Drug Interactions Using Dynamic and Static Mechanistic Models: Delineating Differential CYP3A4 Induction and OATP1B1 Inhibition Potential of Rifampicin

Generation of Enterocyte-Like Cells with Pharmacokinetic Functions from Human Induced Pluripotent Stem Cells Using Small-Molecule Compounds

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