Pharmacokinetics of boldine in control and Mrp2-deficient rats.

The aim of the present study was to describe the currently poorly understood pharmacokinetics (PK) of boldine in control rats (LW, Lewis rats), and Mrp2 transporter-deficient rats (TR(-)). Animals from the LW and TR(-) groups underwent a bolus dose study with 10 mg/kg of boldine applied either orally or intravenously in order to evaluate the major PK parameters. The TR(-) rats demonstrated significantly reduced total clearance with prolonged biological half-life (LW 12+/-4.6 versus TR(-) 20+/-4.4 min), decreased volume of distribution (LW 3.2+/-0.4 l/kg versus TR(-) 2.4+/-0.4 l/kg) and reduced bioavailability (LW 7 % versus TR(-) 4.5 %). Another set of LW and TR(-) rats were used for a clearance study with continuous intravenous administration of boldine. The LW rats showed that biliary and renal clearance formed less than 2 % of the total clearance of boldine. The treatment of samples with beta-glucuronidase showed at least a 38 % contribution of conjugation reactions to the overall clearance of boldine. The TR(-) rats demonstrated reduced biliary clearance of boldine and its conjugates, which was partly compensated by their increased renal clearance. In conclusion, this study presents the PK parameters of boldine and shows the importance of the Mrp2 transporter and conjugation reactions in the elimination of the compound.

Coat colour phenotype, leucopenia, and insulin-dependent diabetes mellitus (IDDM) in BB rats.

Susceptibility to IDDM in BB rats is linked to the MHC and to one or two non-MHC genes. It is postulated that one of the non-MHC genes is leucopenia inherited as autosomal recessive trait which is, at least in part, due to the absence of RT6.1 T lymphocyte subsets. Because the RT6 alloantigenic system is located near the coat colour gene c, we analyzed the coat colour genes of BB rats by production of F1 and F2 hybrids by crossing of three diabetic and leucopenic BB/OK females (RT1u) with one diabetes-resistant and non-leucopenia DA male (RT1av1) genetically defined by the coat colour genotype AABBCCHH. The coat colour phenotype and the RT1.A haplotype were determined in all 144 F2 hybrids. Furthermore, PMNL, body weight gain and plasma glucose were monitored up to an age of 30 weeks of life. At an age of 30 weeks the pancreatic insulin content was determined. The results let us assume that, (a) the coat colour genotype of BB/OK rats is defined as aaBBcchh, (b) the RT6 locus is not responsible for the leucopenia in BB/OK rats and (c) there is a third gene in the diabetes development of BB/OK rats which is probably not linked to one of the coat colour genes.

New congenic rat strains for the separate study of MHC and non-MHC genetic effects in the development of diabetes in BB rats.

Diabetes in BB rats is genetically determined by at least two genes, the one gene mapping to the MHC, the other residing in the genetic background. In order to be able to study the role of MHC and non-MHC genes in diabetogenesis we have established rat strains which combine the diabetes-resistant LEW genetic background with the RT1u haplotype of diabetic BB rats (LEW.1BB) or carry the diabetes-resistant RT1 haplotype of LEW.1A rats on the diabetic BB genetic background (BB.1A). BB rats of two different sublines (BB/OK and BB/PhiK) were used for this purpose. In these rat strains diabetes relevant traits were studied longitudinally, the RT1 haplotypes were analyzed at DNA level and 18 non-MHC linked immunogenetic and enzyme loci were monitored. The results demonstrate the successful transfer of genes with potential relevance for diabetes development in BB rats.

[Proliferation of beta cells after syngeneic transplantation of isolated Langerhans cells into the spleens of diabetic rats]. / Proliferation von Betazellen nach syngener Transplantation isolierter Langerhansscher Inseln in die Milz diabetischer Ratten.

Syngeneic transplantation of cultured and functionally characterized neonatal islet into the spleen of streptozotocin diabetic Lewis rats resulted in long time survival up to 200 days and in plasma glucose levels lower than 9 mmol/l. The daily plasma glucose profile of transplanted rats had shown significantly above that of non diabetic control rats. 200 days after transplantation morphologically intact, insulin containing beta-cells were demonstrable in the spleen, thus demonstrating the long-term survival of functioning islet cells. Proliferation of beta-cells was shown in the transplanted islets. In addition, beta-cell clusters were found which derived from pancreatic ductules transplanted together with the isolated islets into the spleen. Mitose were visible within ductular epithelial cells. The proliferative response of islets after intrasplenic transplantation is probably the result of a long-term stimulation by slightly enhanced plasma glucose values of the transplanted acceptors compared to control animals.