Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice

Tan, Shin Yee; Kan, Elaine; Lim, Wei-Yin; Chay, Grace; Law, Jason H K; Soo, Gian Wan; Bukhari, Nadeem Irfan; Segarra, Ignacio

doi:10.1111/j.2042-7158.2011.01296.x

Cited by 20 publications

(14 citation statements)

References 36 publications

(100 reference statements)

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“…at 60 min after dosing, and then slowly decreased. The imatinib levels in the blood tested were almost consistent with those reported by Tan et al 21) by means of HPLC for imatinib. Using this ELISA, imatinib levels were easily measured in the blood of mice after oral administration.…”

Section: Resultssupporting

confidence: 80%

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Saita

Shin

Fujito

2013

Biological & Pharmaceutical Bulletin

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Imatinib is an oral tyrosine kinase inhibitor used for first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring targeting trough plasma levels of about 1000 ng/mL may help to optimize imantinib's therapeutic effect. This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for a pharmacokinetic evaluation of imatinib. Anti-imatinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin and succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. Enzyme labeling of imatinib with horseradish peroxidase was similarly performed using succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. A simple ELISA for imatinib was developed using the principle of direct competition between imatinib and the enzyme marker for anti-imatinib antibody which had been adsorbed by the plastic surface of a microtiter plate. Serum imatinib concentrations lower than 40 pg/mL were reproducibly measurable using the ELISA. This ELISA was specific to imatinib and showed very slight cross-reactivity (1.2%) with a major metabolite, N-desmethyl imatinib. Using this assay, drug levels were easily measured in the blood of mice after their oral administration of imatinib at a single dose of 50 mg/kg. The specificity and sensitivity of the ELISA for imatinib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of imatinib.

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Section: Resultssupporting

confidence: 80%

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Saita

Shin

Fujito

2013

Biological & Pharmaceutical Bulletin

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“…At therapeutic dosages, imatinib, lapatinib, and sunitinib typically reach plasma concentrations in the range of 5, 4, and 0.3 μM, respectively (Huynh et al, 2017). As shown by data in mice, the concentrations in liver may be higher than in plasma by a factor of 2 for imatinib (Tan et al, 2011) and by a factor of at least 10 for lapatinib (Spector et al, 2015) and sunitinib (Lau et al, 2015), suggesting that toxic liver concentrations can be reached in certain patients. The data of the current study and clinical experience suggest that exposure is an important risk factor for liver toxicity associated with TKIs.…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis

2017

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Tyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM) for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis), all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism), imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib), and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism.

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“…Tan et al reported that when imatinib was administered with metronidazole to mice, the plasma AUC 0 -ϱ was not affected but brain, liver, and kidney exposures were significantly increased (34). Metronidazole coadministration with spiramycin significantly increased spiramycin brain uptake: the brain AUC 0 -ϱ was 67% greater, and the C max increased 72%.…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistic studies in mice have shown that spiramycin bile excretion is mediated by Mrp2 and P-glycoprotein efflux transporters, although P-glycoprotein would play a secondary role (35). Metronidazole may inhibit Mrp2 and P-glycoprotein present at the BBB (14,34) and prevent the efflux of spiramycin, an Mrp2 substrate (35), leading to spiramycin-enhanced brain uptake and higher accumulation to reach efficacious concentrations. The efficiency of this interaction can further be quantified by using the tissue/plasma AUC 0 -ϱ ratio.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, the ability to eradicate brain cysts was assessed in a validated model of chronic toxoplasmosis in mouse (5). The selection of metronidazole was based on its ability to inhibit the efflux pumps and to enhance the brain distribution of other drugs that lack brain penetration (34). In addition, metronidazole has no activity against T. gondii (21); therefore, it was not expected to affect the assessment of spiramycin's effectiveness against brain cysts.…”

mentioning

confidence: 99%

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Significant Reduction of Brain Cysts Caused by Toxoplasma gondii after Treatment with Spiramycin Coadministered with Metronidazole in a Mouse Model of Chronic Toxoplasmosis

Chew

Segarra

Ambu

et al. 2012

Antimicrob Agents Chemother

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Toxoplasma gondii is a parasite that generates latent cysts in the brain; reactivation of these cysts may lead to fatal toxoplasmic encephalitis, for which treatment remains unsuccessful. We assessed spiramycin pharmacokinetics coadministered with metronidazole, the eradication of brain cysts and the in vitro reactivation. Male BALB/c mice were fed 1,000 tachyzoites orally to develop chronic toxoplasmosis. Four weeks later, infected mice underwent different treatments: (i) infected untreated mice (n ‫؍‬ 9), which received vehicle only; (ii) a spiramycin-only group (n ‫؍‬ 9), 400 mg/kg daily for 7 days; (iii) a metronidazole-only group (n ‫؍‬ 9), 500 mg/kg daily for 7 days; and (iv) a combination group (n ‫؍‬ 9), which received both spiramycin (400 mg/kg) and metronidazole (500 mg/kg) daily for 7 days. An uninfected control group (n ‫؍‬ 10) was administered vehicle only. After treatment, the brain cysts were counted, brain homogenates were cultured in confluent Vero cells, and cysts and tachyzoites were counted after 1 week. Separately, pharmacokinetic profiles (plasma and brain) were assessed after a single dose of spiramycin (400

show abstract

Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice

Cited by 20 publications

References 36 publications

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Development of a Specific and Sensitive Enzyme-Linked Immunosorbent Assay for the Quantification of Imatinib

Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis

Significant Reduction of Brain Cysts Caused by Toxoplasma gondii after Treatment with Spiramycin Coadministered with Metronidazole in a Mouse Model of Chronic Toxoplasmosis

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