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. 2020 Oct 14;10:17295. doi: 10.1038/s41598-020-74230-6

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Plasma and regional brain concentration–time profiles. (a) Plasma concentration–time profile of RG 502 H-Big (BUP-Depot) and non-retard formulation. Unpaired t-test showed significant difference between formulations for 2 h (P = 0.0009) but not for 12 h (P = 0.051). (b) Regional brain concentrations of BUP-Depot in mid-and forebrain, medulla oblongata and pons, and cerebellum. (c) Brain-to-plasma ratio-time profiles of BUP-Depot. Brain concentrations are defined as sum of concentrations of mid- and forebrain, medulla oblongata and pons. (d) Specific binding of BUP-Depot and non-retard formulation in brain. Specific binding is defined as difference between combined concentrations of mid- and forebrain, medulla oblongata and pons and concentrations in cerebellum. Unpaired t-test showed significant difference at 2 h (P = 0.01) and 12 h post injection (P = 0.006) between both formulations. BUP-Depot (1.2 mg/kg) and non-retard formulation (0.1 mg/kg) were injected once subcutaneously. Dashed line in all graphs represents threshold of 1 ng/mL or 1 ng/g. Data expressed as mean ± SD. a: 24 h time point of non-retard formulation could not be statistically analyzed as only 2 out of 7 animals showed values higher than LLOQ for concentrations in plasma and cerebellum. Values below LLOQ were excluded, therefore no SD value is shown. (P < 0.05 *; P < 0.01 **).