Significant Decrease in Nelfinavir Systemic Exposure After Omeprazole Coadministration in Healthy Subjects

Fang, Annie; Damle, Bharat; LaBadie, Robert R.; Crownover, Penelope; Hewlett, Dial; Glue, Paul

doi:10.1592/phco.28.1.42

Cited by 34 publications

(29 citation statements)

References 23 publications

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“…A thorough review of the literature since 2006 has yielded additional PPI drug interactions modulated by gastric pH, such as those reported with mycophenolate mofetil [13, 14, 16], the instability of PPIs themselves at low pH [17], and the altered pharmacokinetics of several protease inhibitors (including atazanavir [19], nelfinavir [20], raltegravir [21], ritonavir [22–24], and indinavir [25]). There are, however, a few new CYP-mediated drug interaction studies, with the most notable being the new data on dexlansoprazole and data for interactions between some PPIs and clopidogrel.…”

Section: Discussionmentioning

confidence: 99%

“…For other combinations, the situation may be more complex. Exposure to nelfinavir, which is comparably pH-dependently soluble, was reduced at steady state after nelfinavir 1,250 mg twice daily for 4 days by about 35 % if coadministered with omeprazole 40 mg once daily for 4 days, but terminal elimination and clearance remained unaltered [20]. Nevertheless, nelfinavir is metabolised by CYP 2C19, whose inhibition by omeprazole probably counteracts the loss in exposure caused by solubility effects.…”

Section: Mechanisms Involved In Proton Pump Inhibitor Drug Interactionsmentioning

confidence: 99%

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Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

2014

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Proton pump inhibitors (PPIs) are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. These drug–drug interactions have been previously reviewed. However, the current knowledge is likely to have advanced, so a thorough review of the literature published since 2006 was conducted. This identified new studies of drug interactions that are modulated by gastric pH. These studies showed the effect of a PPI-induced increase in intragastric pH on mycophenolate mofetil pharmacokinetics, which were characterised by a decrease in the maximum exposure and availability of mycophenolic acid, at least at early time points. Post-2006 data were also available outlining the altered pharmacokinetics of protease inhibitors with concomitant PPI exposure. New data for the more recently marketed dexlansoprazole suggest it has no impact on the pharmacokinetics of diazepam, phenytoin, theophylline and warfarin. The CYP2C19-mediated interaction that seems to exist between clopidogrel and omeprazole or esomeprazole has been shown to be clinically important in research published since the 2006 review; this effect is not seen as a class effect of PPIs. Finally, data suggest that coadministration of PPIs with methotrexate may affect methotrexate pharmacokinetics, although the mechanism of interaction is not well understood. As was shown in the previous review, individual PPIs differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole sodium (pantoprazole-Na) have been studied most extensively. Several studies have shown that omeprazole carries a considerable potential for drug interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4. In contrast, pantoprazole-Na appears to have lower potential for interactions with other medications. Lansoprazole and rabeprazole also seem to have a weaker potential for interactions than omeprazole, although their interaction profiles, along with those of esomeprazole and dexlansoprazole, have been less extensively investigated. Only a few drug interactions involving PPIs are of clinical significance. Nonetheless, the potential for drug interactions should be considered when choosing a PPI to manage gastric acid-related disorders. This is particularly relevant for elderly patients taking multiple medications, or for those receiving a concomitant medication with a narrow therapeutic index.

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Section: Discussionmentioning

confidence: 99%

Section: Mechanisms Involved In Proton Pump Inhibitor Drug Interactionsmentioning

confidence: 99%

Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

2014

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“…The maximum plasma concentration of nelfinavir attained with its recommended dosing regimen is approximately 10 M (Fang et al, 2008). Nelfinavir is reported to be highly bound to plasma proteins, and the free concentrations attained during therapy may be much lower than the IC 50 reported for its inhibition of BCRP-mediated transport.…”

Section: Downloaded Frommentioning

confidence: 97%

Substrate-Dependent Breast Cancer Resistance Protein (Bcrp1/Abcg2)-Mediated Interactions: Consideration of Multiple Binding Sites in in Vitro Assay Design

Giri¹,

Agarwal

Shaik

et al. 2008

Drug Metab Dispos

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ABSTRACT:In vitro assays are frequently used for the screening of substrates and inhibitors of transporter-mediated efflux. Examining directional flux across Madin-Darby canine kidney (MDCK) II cell monolayers that overexpress a transporter protein is particularly useful in identifying whether or not a candidate compound is an inhibitor or substrate for that transport system. Studies that use a single substrate or inhibitor in competition assays can be challenging to interpret because of the possible multiple mechanisms involved in substrate/inhibitor-protein interactions. During our previous studies of substrate-inhibitor-transporter interactions, we observed differences in breast cancer resistance protein (BCRP) inhibition, depending on the substrate and the inhibitor. Therefore, we investigated BCRP-mediated interactions with a 4 ؋ 4 matrix of substrates and inhibitors using monolayers formed from MDCKII cells transfected with murine BCRP (Bcrp1/Abcg2). The selective BCRP inhibitor 3-(6-isobutyl- Multidrug resistance observed in cancer therapy is commonly attributed to ATP-binding cassette (ABC) efflux transporter proteins, such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP). These ABC transport proteins are localized not only in drug-resistant cancer cells, but also in the plasma membranes of epithelial cells in various normal tissues such as intestine, liver, kidney, placenta, and the blood-brain barrier where they can influence absorption, distribution, metabolism, and excretion of their substrates (Leslie et al., 2005). The efflux transport protein BCRP is expressed in various organs, and because of its transmembrane orientation, this transporter is able to extrude substrates out of the cell (Maliepaard et al., 2001). BCRP is considered a half-transporter because of the presence of only six transmembrane domains, and it has been shown to exist in a multisubunit oligomeric structure that may be critical for its function (Bhatia et al., 2005).Numerous in vitro studies have characterized substrate-transporter interactions and these effects have also been observed in vivo (Merino et al., 2006;Shaik et al., 2007). Interaction of BCRP with various substrate molecules in vitro and in vivo has provided evidence that BCRP-mediated efflux could play a major role in the absorption, distribution, metabolism, and excretion of its substrate molecules (Staud and Pavek, 2005). Identifying inhibitors that modulate BCRPmediated efflux of substrates could be valuable in enhancing target exposure to the drug. Various molecules have been shown to have inhibitory effects on BCRP-mediated transport of its substrates. GF120918 is a potent P-gp inhibitor that was shown to also have an inhibitory effect on BCRP-mediated transport. For instance, GF120918 inhibits BCRP-mediated transport of abacavir, zidovudine, STI-571 (imatinib), and prazosin (Breedveld et al., 2005;Ejendal and Hrycyna, 2005;Pan et al., 2007). Fumitremorgin C was identified as the first select...

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“…Nelfinavir forms an active metabolite (M8) through CYP2C19. Omeprazole is known to be a competitive inhibitor of CYP2C19 and has been associated with a 92% reduction in the M8 metabolite [115]. Use of proton pump inhibitors and nelfinavir together should be avoided.…”

Section: Antiretroviral-non-antiretroviral Interactionsmentioning

confidence: 99%

Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

Rathbun

Liedtke

2011

Pharmaceutics

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Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

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Significant Decrease in Nelfinavir Systemic Exposure After Omeprazole Coadministration in Healthy Subjects

Cited by 34 publications

References 23 publications

Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

Substrate-Dependent Breast Cancer Resistance Protein (Bcrp1/Abcg2)-Mediated Interactions: Consideration of Multiple Binding Sites in in Vitro Assay Design

Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

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