Primary human hepatocytes as a tool for the evaluation of structure—activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin

Li, Albert P.; Reith, Margaret; Rasmussen, Anders Mølgaard; Gorski, J. Christopher; Hall, Stephen D.; Xu, Lilly; Kaminski, Donald L.; Cheng, Lawrence K.

doi:10.1016/s0009-2797(97)00071-9

Cited by 146 publications

(83 citation statements)

References 19 publications

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“…Compounds used as negative controls were ␤-naphthoflavone, methotrexate, methylprednisolone, clarithromycin, roxithromycin, and probenecid (Pichard et al, 1992;Ledirac et al, 2000;Luo et al, 2002;Madan et al, 2003). Compounds used as positive controls were mifepristone, troglitazone, carbamazepine, dexamethasone, efavirenz, rosiglitazone, clotrimazole, avasimibe, ritonavir, phenytoin, pioglitazone, phenobarbital, reserpine, rifabutin, sulfinpyrazone, nifedipine, rifapentine, and rifampicin (Kocarek et al, 1995;Li et al, 1997;Drocourt et al, 2001;Luo et al, 2002;Madan et al, 2003;Sahi et al, 2003a,b;Hariparsad et al, 2004). Fa2N-4 cells were treated for 2 days with varying concentrations of test compounds and CYP3A4 mRNA was measured.…”

Section: Characterization Of Fa2n-4 Cells Using Positive and Negativementioning

confidence: 99%

Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction

Ripp¹,

Mills²,

Fahmi³

et al. 2006

Drug Metab Dispos

114

106

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ABSTRACT:Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result in decreased exposure to coadministered drugs, with potential loss of efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool to identify CYP3A4 inducers. The purpose of the current studies was to characterize the effect of known inducers on CYP3A4 in Fa2N-4 cells, and to determine whether these in vitro data could reliably project the magnitude of DDIs caused by induction. Twenty-four compounds were chosen for these studies, based on previously published data using primary human hepatocytes. Eighteen compounds had been shown to be positive for induction, and six compounds had been shown to be negative for induction. In Cytochrome P4503A4 (CYP3A4) is the major drug-metabolizing enzyme in human liver and is responsible for the clearance of many commonly used drugs, including benzodiazepines, statins, calcium channel blockers, and HIV protease inhibitors. Certain drugs can modulate the level of CYP3A4 activity, thereby causing changes in clearance of coadministered drugs that are CYP3A4 substrates. Levels of CYP3A4 activity can be decreased by inhibition of enzyme activity, or increased by induction of new protein synthesis. Changes in CYP3A4 activity, either through inhibition or induction, can result in potentially serious drug-drug interactions (DDIs). Whereas assays for evaluating inhibition of CYP3A4 are routine and the relationship between in vitro data and in vivo effects relatively well understood (Bjornsson et al., 2003), assays for evaluating induction are less well characterized and the relationships between in vitro and in vivo data less clear.Induction of CYP3A4 is thought to occur primarily through transcriptional activation of the gene. The 5Ј-regulatory region of the CYP3A4 gene contains elements that bind various transcription factors that can up-or down-regulate transcription. One such transcription factor is the pregnane X receptor (PXR). PXR is a ligand-activated transcription factor that is activated by a variety of drugs and endogenous compounds to increase transcription of CYP3A4 as well as other drug-metabolizing enzymes and transporters (Kliewer et al., 2002). Most drugs that induce levels of CYP3A4 are thought to do so primarily via PXR activation, e.g., rifampicin, phenytoin, hyperforin, and clotrimazole (Lehmann et al., 1998). There are several in vitro tools for assessment of CYP3A4 induction. To this point, primary human hepatocyte cultures have been considered the gold standard for in vitro induction assessment (Madan et al., 2003). Primary hepatocytes are typically treated with test compound for 2 or 3 days; then, CYP3A4 levels are compared with those in vehicle-treated cells. CYP3A4 expression can be evaluated by measuring enzymatic activity with a selective probe substrate or by measuring CYP3A4 mRNA. Primary hepatocytes are considered a reliable way to assess induction; however, ability to atta...

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Section: Characterization Of Fa2n-4 Cells Using Positive and Negativementioning

confidence: 99%

Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction

Ripp¹,

Mills²,

Fahmi³

et al. 2006

Drug Metab Dispos

114

106

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“…The treatment is more complex, takes longer or has to include drugs that are more expensive or unavailable. Rifabutin has been recommended because of fewer drug-drug interactions, but this alternative is not generally available in resource-poor settings [25]. A non-rifamycincontaining regimen that can be used comprises isoniazid and ethambutol, given for a minimum of 12-18 months, supplemented by pyrazinamide during at least the first 2 months of treatment [15].…”

Section: Treatment Of Tuberculosis In Hiv-infected Patients Starting mentioning

confidence: 99%

Should tuberculosis treatment and control be addressed differently in HIV-infected and -uninfected individuals?

Dlodlo¹

2005

Eur Respir J

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Infection with HIV drives the tuberculosis epidemic, especially in sub-Saharan Africa, where up to 75% of individuals with tuberculosis are co-infected with HIV. This article reviews the epidemiological link between the conditions, how tuberculosis diagnosis and treatment differ between HIV-infected versus -uninfected individuals and the span of additional measures required to prevent and control HIV-related tuberculosis.Tuberculosis chemotherapy using standard short-course regimens is highly effective in both groups, and treatment follows the same principles. It differs in certain aspects, such as when antiretroviral treatment should be started in HIV-infected individuals with tuberculosis and consideration of drug-drug interactions between the rifamycins and certain antiretroviral drugs.Control of HIV-related tuberculosis requires, fundamentally, control of HIV transmission. Meanwhile, it is necessary to make concentrated efforts to intensify high-quality tuberculosis services employing the directly observed treatment, short-course (DOTS) strategy, carry out extensive research towards an evidence-based model for the expanded scope of collaborative tuberculosis and HIV/AIDS interventions, and ensure efficient implementation of the findings and recommended policies.The challenge is gigantic, and both robust within-country and international leadership and competent management capabilities will be required, in addition to substantial human and financial resources.

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“…The isoform CYP3A4 is particularly important as it is the main enzyme responsible for the metabolism of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI). Amongst the most potent inducers of CYP3A4 [156,157] are the rifamycin family and rifampicin (table 2) is the most powerful inducer of CYP3A4 known, with rifabutin less so (table 3) [158]. Rifampicin also induces other cytochromes such as CYP2C19 and CYP2D6 and increases activity of the drug transporter Pglycoprotein that contributes to the absorption, distribution and elimination of PI [159,160].…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

“…Rifampicin also induces other cytochromes such as CYP2C19 and CYP2D6 and increases activity of the drug transporter Pglycoprotein that contributes to the absorption, distribution and elimination of PI [159,160]. Rifabutin, unlike rifampicin, is also a substrate of the CYP3A4 enzyme [156] thus CYP3A4 inhibitors will increase the concentration of rifabutin but have no effect on rifampicin metabolism. As HIV-1 PI are inhibitors of CYP3A4, plasma concentrations of rifabutin and its metabolites may increase and cause toxicity when used with PI [161].…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Clinical management of tuberculosis and HIV-1 co-infection

Schutz¹,

Meintjes²,

Almajid³

et al. 2010

Eur Respir J

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In many parts of the world the commonest serious opportunistic infection that occurs in HIV-1 infected persons is tuberculosis (TB). HIV-1 co-infection modifies the natural history and clinical presentation, and adversely affects the outcome of TB. Severe disseminated disease is well-recognised but it is increasingly appreciated that early disease characterised by very few or no symptoms is also common. Immunodiagnostic methods to ascertain latent TB in HIV-1 infected persons are compromised in sensitivity.Chemoprevention of HIV-1-associated TB is effective, its benefits are restricted to those which have evidence of immune sensitisation and appear short-lived in areas of high TB burden. Although promising advances in the microbiological diagnosis of TB have recently occurred, the diagnosis of HIV-1-associated TB remains difficult because of more frequent presentation as sputum negative or extrapulmonary disease.Management of co-infected patients can be complex because of overlapping drug toxicities and interactions. Nevertheless consensus is developing that antiretroviral therapy should be provided as soon as practicable after starting TB treatment in HIV-1 co-infected persons. This has the consequence of increasing the frequency of immune reconstitution inflammatory syndrome, the pathogenesis and management of which is poorly defined.

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Primary human hepatocytes as a tool for the evaluation of structure—activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin

Cited by 146 publications

References 19 publications

Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction

Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction

Should tuberculosis treatment and control be addressed differently in HIV-infected and -uninfected individuals?

Clinical management of tuberculosis and HIV-1 co-infection

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