The use of the effective antineoplastic agent cisplatin is limited by its serious side effects , such as oto-and nephrotoxicity. Ototoxicity is a problem of special importance in children , because deafness hampers their language and psychosocial development. Recently , organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study , we investigated in an in vivo model the role of OCTs in the development of cisplatin oto-and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose , water , and protein) and hearing (auditory brainstem response) were studied in wildtype and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore , cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs , indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.

Purpose To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents gadodiamide (a linear contrast agent) or gadoterate (a macrocyclic contrast agent). Materials and Methods Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI (n = 140 rats, corresponding to seven time points, two contrast agents, and 10 rats per group). Animals were sacrificed at 1 week, 1 month, and 2, 3, 4, 5, and 12 months after the last injection. Brain and plasma were sampled to determine the total gadolinium concentration by using inductively coupled plasma mass spectrometry (ICP-MS). For the cerebellum, gadolinium speciation analysis was performed after mild extraction at four time points (1 month and 3, 5, and 12 months after the last injection) by using size exclusion chromatography and hydrophilic interaction liquid chromatography, both coupled to ICP-MS. Tissue gadolinium kinetics were fitted to estimate the area under the curves and tissue elimination half-lives over the 12-month injection-free period. Results T1 hyperintensity of the deep cerebellar nuclei was observed only in gadodiamide-treated rats and remained stable from the 1st month after the last injection (the ratio of the signal intensity of the deep cerebellar nuclei to the signal intensity of the brain stem at 1 year: 1.101 ± 0.023 vs 1.037 ± 0.022 before injection, P < .001). Seventy-five percent of the total gadolinium detected after the last injection of gadodiamide (3.25 nmol/g ± 0.30) was retained in the cerebellum at 1 year (2.45 nmol/g ± 0.35), with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with gadoterate, consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels (0.07 nmol/g ± 0.03). Conclusion After repeated administration of gadodiamide, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of gadoterate, only traces of the intact chelated gadolinium were observed with time-dependent clearance. Online supplemental material is available for this article.

A rapid and sensitive method for the species-selective determination of chromlum(III) and chromlum(VI) In water samples by flame atomic absorption spectrometry using online preconcentration on a microcolumn packed with activated alumina (acidic form) has been developed. Sequential species-selective sorption was possible by using the Clark-Lubs buffer systems with pH 7 for Cr(III) and pH 2 for Cr-(VI). The preconcentrated species were eluted directly from the column to the nebulizer-burner system using 1.0 mol/L nitric acid and 0.5 mol/L ammonia for Cr(III) and Cr(VI), respectively. The retention efficiency was better than 80%for Cr(III) and better than 90 % for Cr(VI), giving a sensitivity enhancement of 25 for a 3-mL sample loading. The effect of concomitant species was Investigated, and satisfactory recovery of 90-106% could be obtained from natural water samples. Linear calibration for both species was established over the concentration range 10-200 pg/L• with detection limits (3 s) of 1.0 and 0.8 pg/L• for Cr(III) and Cr(VI), respectively.

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