PET-Evaluated Transport of [11C]Hydroxyurea Across the Rat Blood-Brain Barrier - Lack of Influence of Cyclosporin and Probenecid
Uppsala Imanet, GE Healthcare, P.O. Box 967, SE-751 85 Uppsala, Sweden.
Drug metabolism letters
09/2007; 1(3):189-94. DOI: 10.2174/187231207781369799
The transport of hydroxyurea, a ribonucleoside reductase inhibitor, over biological membranes is slow and it has therefore been suggested that the substance could interact with an active efflux transporter. The transport of [(11)C]hydroxyurea into the rat brain was therefore studied after administration of the multidrug resistance protein inhibitor probenecid (50 and 150 mg/kg), the P-glycoprotein inhibitor cyclosporin A (25 mg/kg), hydroxyurea (50, 150 and 450 mg/kg) and mannitol (25%). None of the intervention drugs affected the brain uptake of [(11)C]hydroxyurea. The brain-to-plasma concentration ratios (K(p)), with or without intervention drug, were in the range 0.12-0.25 after 60 min of [(11)C]hydroxyurea infusion. [(11)C]Verapamil, a P-glycoprotein substrate with low brain penetration, was used to study the ability of hydroxyurea to inhibit P-glycoprotein. Administration of hydroxyurea (150 and 450 mg/kg) did not increase brain concentrations of [(11)C]verapamil. It is therefore unlikely that hydroxyurea is a substrate for or an inhibitor of P-glycoprotein or a substrate for a probenecid sensitive transport system. The low brain concentrations may instead be the result of slow uptake due to the hydrophilic nature of hydroxyurea.
Available from: Kaushik Thanki
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ABSTRACT: The present report focuses on the various aspects of the oral delivery of anticancer drugs. The significance of oral delivery in cancer therapeutics has been highlighted which principally includes improvement in quality of life of patients and reduced health care costs. Subsequently, the challenges incurred in the oral delivery of anticancer agents have been specially emphasized. Sincere efforts have been made to compile the various physicochemical properties of anticancer drugs from either literature or predicted in-silico via GastroPlus™. The later section of paper reviews various emerging trends to tackle the challenges associated with oral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipients- and nanocarrier based- approaches. The role of drug nanocrystals and various others such as polymer based- and lipid based- nanocarriers in the bioavailability enhancement along with their clinical outcomes have also been discussed exhaustively. Furthermore, an insight on the various absorption mechanisms of these nanocarriers across the gastrointestinal tract has also been highlighted.
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Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expanded our studies in a xenograft orthotopic mouse model.
Six women and 1 man, aged 26-76 years (median, 56 years), with magnetic resonance imaging-proven progression of ≥25% in cross-sectional area of recurrent meningioma (2 World Health Organization grade I, 5 grade II) within the preceding 6 months received HU 1000 or 1500 mg/day (20 mg/kg/day, twice daily) as well as verapamil sustained-release tablets with dose escalation every 2 weeks (120-240 mg/day). They underwent magnetic resonance imaging every 3 months during therapy. To augment the clinical trial results, we performed mouse orthotopic xenograft experiments using similar dosing to test tumor growth, vascularity, and drug bioavailability.
After a mean of 8.1 cycles of treatment, the patients demonstrated no significant radiographic responses during mean follow-up of 14.5 ± 4.8 months. Median progression-free survival (PFS) was 8.0 months, and 6-month PFS was 85%. Side effects occurred in 6 (86%) patients. Xenograft studies showed no effect of individual or combined treatments on meningioma growth. Neither HU nor verapamil was detectable in mouse brain tumor tissue despite adequate serum levels within therapeutic ranges.
Our results showed no effect of HU or verapamil on tumor recurrence, PFS, and in vivo tumor burden reduction. Drug delivery to the tumor may be a major limitation.
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