Methods: The tissue distribution and brain uptake as well as the metabolic profile of [I-123]-FMIP in wild-type

and mdr1a (-/-) mice after pretreatment with physiological saline or cyclosporin A (CsA) (50 mg/kg) was investigated. The influence of increasing doses CsA on brain uptake of [I-123]-FMIP was explored. mu SPECT images of mice brain after injection of 11.1 MBq [I-123]-FMIP were obtained for different treatment strategies thereby using the Milabs U-SPECT-II.

Results: Modulation of P-gp with CsA (50 mg/kg) as well as mdr1a gene depletion resulted in significant increase in cerebral uptake of [I-123]-FMIP with only minor effect on blood activity. [I-123]-FMIP is relative https://www.selleckchem.com/products/acalabrutinib.html stable in vivo with >80% intact [I-123]-FMIP in brain at 60 min p.i. in the different treatment regiments. A dose-dependent sigmoidal increase in brain uptake of [I-123]-FMIP with increasing doses of CsA was observed. In vivo region of interest-based SPECT measurements correlated well with the observations of the biodistribution studies.

Conclusions: These findings indicate that [I-123]-FMIP can be applied to assess the efficacy of newly developed P-gp modulators. It is also suggested

that [I-123]-FMIP is a promising SPECT tracer for imaging P-gp at the blood-brain barrier. (C) 2010 Published by Elsevier Inc.”
“The renal distal convoluted tubule (DCT) has an Lazertinib ic50 Diflunisal essential role in maintaining systemic magnesium (Mg2+) concentration. The DCT is the final determinant of plasma Mg2+ levels, as the more distal nephron segments are largely impermeable to Mg2+. In the past decade, positional candidate strategies in families with inherited forms of hypomagnesemia have led to the identification of genes involved in Mg2+ handling. A large fraction of this resides in the DCT, namely, (i) the transient receptor potential channel melastatin subtype 6 (TRPM6), a divalent cation-permeable channel located at the luminal membrane of the DCT, facilitates Mg2+ entry from the pro-urine into the cell; (ii) the epidermal

growth factor is a novel hormone regulating active Mg2+ transport through TRPM6; (iii) the voltage-gated K+ channel, Kv1.1, establishes a favorable luminal membrane potential for TRPM6-mediated Mg2+ transport; (iv) the Na+/K+-ATPase gamma-subunit (gamma-Na+/K+-ATPase) was identified as mutated protein in a family with isolated dominant hypomagnesemia. The molecular mechanism by which gamma-Na+/K+-ATPase is involved in DCT Mg2+ handling remains unknown; (v) a high percentage of patients with mutations in the renal transcription factor HNF1B (hepatocyte nuclear factor 1 homeobox B) gene develop hypomagnesemia; and (vi) Gitelman and EAST/SeSAME syndrome patients suffer from a similar tubulopathy due to mutations in NCC (NaCl cotransporter) and Kir4.1, respectively.