Effects of Uptake and Efflux Transporter Inhibition on Erythromycin Breath Test Results

Frassetto, LA; Poon, Steve F.; Tsourounis, Candy; Valera, C; Benet, Leslie Z.

doi:10.1038/sj.clpt.6100148

Cited by 48 publications

(61 citation statements)

References 22 publications

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“…As shown by Frassetto, the erythromycin breath test may be confounded by CRF induced changes in the drug transporters OATP) and Pgp which control the intracellular pool of erythromycin in the hepatocytes [89]. Nolin showed an increase in EBT post hemodialysis compared to predialysis indicating a dialyzable uremic factor may be inhibiting erythromycin metabolism [90].…”

Section: Effect Of Altered Drug Transport On Interpretation Of Pharmamentioning

confidence: 99%

The effect of chronic renal failure on drug metabolism and transport

Dreisbach

Lertora

2008

Expert Opinion on Drug Metabolism & Toxicology

210

154

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Background-Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine.Objectives-The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport.Methods-The National Library of Medicine PubMed was utilized with the search terms 'chronic renal failure, cytochrome P450, liver metabolism, efflux drug transport and uptake transport' including relevant articles back to 1969.Results-Animal studies in CRF have shown a major downregulation (40-85%) of hepatic and intestinal cytochrome P450 (CYP) metabolism. High levels of parathyroid hormone, cytokines, and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein (Pgp) and organic anion transporting polypeptide (OATP) are also affected.Conclusion-CRF alters intestinal, renal, and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

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Section: Effect Of Altered Drug Transport On Interpretation Of Pharmamentioning

confidence: 99%

The effect of chronic renal failure on drug metabolism and transport

Dreisbach

Lertora

2008

Expert Opinion on Drug Metabolism & Toxicology

210

154

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“…The low therapeutic index of cyclosporine makes it an undesirable probe substrate in vivo (Jorga et al, 2004). Erythromycin is often used in a single time point breath test (Frassetto et al, 2007), limiting the amount of clinical DDI data available for a full time course, and may exhibit confounding transporter activity . These characteristics hindered our ability to create a direct correlation between the in vitro and in vivo data for cyclosporine and erythromycin and were part of the rationale for excluding them from consideration as alternate probe substrates.…”

Section: Alternative Cyp3a4 Ddi Probe Substratesmentioning

confidence: 99%

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Foti¹,

Rock²,

Wienkers³

et al. 2010

Drug Metab Dispos

117

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ABSTRACT:Understanding the potential for cytochrome P450-mediated drugdrug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine/nifedipine, and testosterone. However, the design of clinical CYP3A4 DDI studies may be confounded for cases such as 1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458), with which testosterone is predicted to exhibit a clinically relevant DDI whereas midazolam and felodipine/nifedipine are not. To develop an appropriate path forward for such clinical DDI studies, the inhibition potency of 20 known inhibitors of CYP3A4 were measured in vitro using 8 clinically relevant CYP3A4 probe substrates and testosterone. Hierarchical clustering suggested four probe substrate clusters: testosterone; felodipine; midazolam, buspirone, quinidine, and sildenafil; and simvastatin, budesonide, and fluticasone. The in vivo sensitivities of six clinically relevant CYP3A4 probe substrates (buspirone, cyclosporine, nifedipine, quinidine, sildenafil, and simvastatin) were determined in relation to midazolam from literature DDI data. Buspirone, sildenafil, and simvastatin exhibited similar or greater sensitivity than midazolam to CYP3A4 inhibition in vivo. Finally, Simcyp was used to predict the in vivo magnitude of CYP3A4 DDIs caused by AMG 458 using midazolam, sildenafil, simvastatin, and testosterone as probe substrates.The cytochrome P450 (P450) superfamily of drug-metabolizing enzymes is involved in the metabolism of the majority of currently prescribed drugs and new chemical entities. Within the P450 superfamily, CYP3A4 is responsible for the metabolism of approximately 55% of marketed drugs (Wienkers and Heath, 2005). Because of its general importance in drug clearance, assessment and modeling of CYP3A4 inhibition are a critical part of the drug discovery and development process. Probe substrate-dependent inhibition profiles have been observed in vitro with CYP3A4, possibly owing to the presence of multiple probe substrate binding regions within the CYP3A4 active site (Kenworthy et al., 1999). In response, a standard approach when testing for CYP3A4 inhibition has been to use multiple probe substrates such as midazolam (the clinical standard), felodipine/nifedipine, or testosterone for in vitro experiments (Wienkers and Heath, 2005). Extrapolation of the in vitro data to the in vivo situation may be confounded in the multiple probe substrate scenario if a probe substrate that is not clinically relevant, such as testosterone, is markedly more susceptible to inhibition than midazolam (the clinical standard) and felodipine/nifedipine . Our first a...

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“…A recent clinical study suggests that the role of uptake and efflux transporters in the disposition of erythromycin could complicate the interpretation of the results (Frassetto et al, 2007). A similar methodology has been tested successfully for CYP1A2-mediated caffeine N-demethylation (Rost et al, 1992).…”

mentioning

confidence: 99%

In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective

Chu¹,

Einolf²,

Evers³

et al. 2009

Drug Metab Dispos

153

122

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ABSTRACT:Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies. In this article, a team of 10 scientists from nine Pharmaceutical Research and Manufacturers of America (PhRMA) member companies conducted an anonymous survey among PhRMA companies to query current practices with regards to the conduct of in vitro induction assays, data interpretation, and clinical induction study practices. The results of the survey are presented in this article, along with reviews of current methodologies of in vitro assays and in vivo studies, including modeling efforts in this area. A consensus recommendation regarding common practices for the conduct of P450 induction studies is included.The convergence of recent advances in molecular biology and genomics, higher throughput chemical synthesis, and automated highthroughput in vitro enzyme and cell-based assays to assess biological activity has led to shorter lead identification and optimization times in drug research. However, these breakthroughs have not yet translated into success in drug development. Surveys suggest that in the last several years, the number of New Drug Applications submitted to regulatory agencies has declined and that the poor success rate during drug development is to some extent due to late-stage failures. It is important that novel and innovative approaches are used for assessing the risks and benefits of new molecular entities (NMEs) early in the research and development life cycle to minimize late-stage attrition.Based on a survey conducted in 2004, the major factors for compound attrition during clinical development are lack of efficacy, toxicity, and safety, and suboptimal pharmacokinetics and/or bioavailability, with the remaining failures due to financial and/or commercial reasons (Kola and Landis, 2004). In that survey, one notable observation was the reduction of compound attrition due to pharmacokinetic and/or bioavailability issues from pre-1991 to the period be- ABBREVIATIONS: NME, new molecular entity; P450, cytochrome P450; DDI, drug-drug interaction; RIF, rifampicin; PhRMA, Pharmaceutical Research and Manufacturers of America; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; UGT, uridine diphosphate glucuronosyl transferase; FXR, farnesyl X receptor; PPAR, peroxisome proliferator-activated receptor; VDR, vitamin D receptor; Nrf2, nuclear factor erythroid 2-related factor 2; LBD, ligand binding domain; hPXR, human PXR; SR12813, tetra-ethyl 2-(3,5-di-tertbutyl...

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Effects of Uptake and Efflux Transporter Inhibition on Erythromycin Breath Test Results

Cited by 48 publications

References 22 publications

The effect of chronic renal failure on drug metabolism and transport

The effect of chronic renal failure on drug metabolism and transport

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective

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