Hubensack, Martina and Mueller, Christine and Hoecherl, Peter and Fellner, Stephan and Spruss, Thilo and Bernhardt, Guenther and Buschauer, Armin (2008) Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 134 (5). pp. 597-607. ISSN 0171-5216,
Full text not available from this repository. (Request a copy)Abstract
Purpose Previously, we studied the effect of co-administration of paclitaxel with the second generation ABCB1 (p-gp) modulator valspodar on the intracerebral growth of human U118-MG glioblastoma in nude mice. Valspodar significantly increased the brain levels of paclitaxel by inhibition of p-gp expressed at the blood brain barrier. Thus, the tumour burden was reduced by 90%, which was considered as a proof of concept. However, the paclitaxel dose had to be reduced because of toxic side effects resulting from increased drug levels due to p-gp modulation in peripheral tissues. Therefore, in the present study we examined the co-application of paclitaxel with the third generation ABCB1 modulators elacridar and tariquidar, which were supposed to preferentially modulate p-gp in brain capillaries. Methods The inhibitory activity of the modulators was measured by a flow cytometric and a chemosensitivity assay in vitro. To determine the distribution of paclitaxel in vivo, nude mice received 50 mg/kg of valspodar, elacridar or tariquidar p.o. (control: vehicle) 4 h before i.v. injection of 8 mg/kg of paclitaxel. Brain, liver, kidney and plasma were collected and analyzed by RP-HPLC. Results Our in vitro experiments demonstrate that the new modulators are about 80 times more effective in comparison to valspodar. Co-administration of paclitaxel with elacridar and tariquidar led to a long lasting fivefold increase in the concentration of the cytostatic in the brain. Although the increase (2.5- to 7-fold) tended to be lower compared to that induced by co-administered valspodar (six- to eightfold), the brain/plasma ratios achieved with the new modulators were 2-15 times higher. Conclusions Elacridar and tariquidar seem to modulate p-glycoprotein preferentially at the blood-brain barrier. Our results suggest that the systemic toxicity of cytostatics combined with elacridar or tariquidar should be lower than in combination with valspodar.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BLOOD-BRAIN-BARRIER; P-GLYCOPROTEIN INHIBITOR; MEDIATED MULTIDRUG-RESISTANCE; CENTRAL-NERVOUS-SYSTEM; IN-VIVO REVERSAL; ORAL BIOAVAILABILITY; PHARMACOKINETIC PROPERTIES; CYTOCHROME-P450 3A; GF120918; VITRO; blood brain barrier; ABCB1; P-glycoprotein 170; valspodar; elacridar; tariquidar; paclitaxel |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Nov 2020 10:02 |
| Last Modified: | 03 Nov 2020 10:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30961 |
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