Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100

Smith, Norman E.; Baker, Sharyn D.; Gonzalez, Frank J.; Harris, James W.; Figg, William D.; Sparreboom, Alex

doi:10.1038/sj.bjc.6604353

Cited by 24 publications

(20 citation statements)

References 17 publications

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“…2) to determine the extent of alterations in the pharmacokinetic profile of erlotinib. Erlotinib demonstrated an erratic absorption pattern which is consistent with previous reports on murine pharmacokinetics [25, 26]. Due to this erratic pattern, the half-life and oral apparent clearance were not consistently estimated across all experimental conditions and therefore is not discussed.…”

Section: Resultssupporting

confidence: 82%

“…The metabolic fate of OSI-420 has only been attributed to CYP3A4 in the literature, albeit other CYP450 s may be involved further confounding the results [31]. It should also be noted that the metabolite/parent drug ratio of ~29 % for the control arm is similar to prior experiments utilizing mice [25] but is still fivefold higher than that reported in the mass balance study and human hepatocyte experiment [19, 31]. Therefore, the alterations noted in mice may not be reflective of humans.…”

Section: Discussionmentioning

confidence: 63%

“…Dose formulation was sonicated for 5 min and vortex-mixed for 5–10 min prior to administration. Erlotinib was administered in the presence and absence of dexamethasone, efavirenz, ketoconazole, or ritonavir by oral gavage at a dose of 50 mg/kg [25, 26]. Dexamethasone and efavirenz were administered by oral gavage daily for 4 days with the last dose occurring approximately 45 min prior to erlotinib administration to ensure CYP3A4 induction.…”

Section: Methodsmentioning

confidence: 99%

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Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

Deeken

Beumer

Anders

et al. 2015

Cancer Chemother Pharmacol

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Purpose Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib. Methods Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC). Results Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure. Conclusion CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

Deeken

Beumer

Anders

et al. 2015

Cancer Chemother Pharmacol

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“…We next tested CB-839 alone or in combination with erlotinib on HCC827 mouse xenografts. We dosed mice with erlotinib concentrations of between 5-12.5mg/kg in order to maintain plasma concentrations of erlotinib in mice that mirror a clinically achievable range of ∼1.2ug/mL in patients (Hidalgo et al, 2001; Smith et al, 2008). When tumors reached a size of 200-300mm 3 on day 28 post-implantation, mice were acutely treated for 6 days with vehicle (Veh), CB-839 (CB) (200mg/kg), Erlotinib (E) (12.5mg/kg), or combination Erlotinib and CB-839 (E+CB) (Figures 1C, 1D).…”

Section: Resultsmentioning

confidence: 99%

Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer

et al. 2017

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Cancer cells exhibit increased use of nutrients including glucose and glutamine to support the bioenergetic and biosynthetic demands of proliferation. We tested the small molecule inhibitor of glutaminase CB-839 in combination with erlotinib on EGFR mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMPK pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-Glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following CB-839 + erlotinib treatment. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.

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“…Administration of BAS 100, a novel mechanism-based CYP3A4 inhibitor isolated from grapefruit juice, resulted in a 2.1-fold increase in erlotinib systemic exposure following oral administration to wild-type and humanized CYP3A4 transgenic mice [223]. This study demonstrates that grapefruit juice may increase the low and variable oral bioavailability of erlotinib in cancer patients.…”

Section: Erlotinib + Dietary/herbal Supplementsmentioning

confidence: 94%

Herbal Interactions with Anticancer Drugs: Mechanistic and Clinical Considerations

Yang

Liu

et al. 2010

CMC

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A large number of herbal remedies (e.g. garlic, mistletoe, Essiac, Lingzhi, and astragalus) are used by cancer patients for treating the cancer and/or reducing the toxicities of chemotherapeutic drugs. Some herbal medicines have shown potentially beneficial effects on cancer progression and may ameliorate chemotherapy-induced toxicities. However, there is no or weak scientific basis for the clinical use of these herbal medicines in cancer management and almost none of these plant medicines have been tested in rigorous clinical trials. There are increased reports on the interaction of herbal medicines and anticancer drugs that is becoming a safety concern. For example, a clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, 2 weeks of treatment with St John's wort at 900 mg/day significantly decreased the systemic exposure of imatinib by 32%. In women with advanced breast cancer, coadministration of garlic supplement reduced the clearance of docetaxol by 23.1-35.1%, although the difference did not achieve statistical significance. Most anticancer drugs undergo Phase I and/or II metabolism and are substrates of P-glycoprotein, breast cancer resistance protein, multidrug resistance associated proteins, and/or other transporters. Induction and inhibition of these enzymes and transporters is considered an important mechanism for herb-anticancer drug interactions. Further studies are warranted to investigate potentially harmful herbal interactions with anticancer drugs in patients.

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Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100

Cited by 24 publications

References 17 publications

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer

Herbal Interactions with Anticancer Drugs: Mechanistic and Clinical Considerations

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