Effect of mTOR inhibitor on body weight: from an experimental rat model to human transplant patients

• Published in: Transplant international Vol. 21; no. 10; pp. 992 - 998
• Main Authors: Rovira, Jordi, Marcelo Arellano, Edgar, Burke, James T., Brault, Yves, Moya‐Rull, Daniel, Bañón‐Maneus, Elisenda, Ramírez‐Bajo, María J., Gutiérrez‐Dalmau, Alex, Revuelta, Ignacio, Quintana, Luis F., Campistol, Josep M., Diekmann, Fritz
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2008
• Subjects: Adipocytes - drug effects; Adipocytes - pathology; Animals; Body Mass Index; Body Weight - drug effects; Cyclosporine - therapeutic use; Disease Models, Animal; Graft Rejection - metabolism; Graft Rejection - pathology; Graft Rejection - prevention & control; Humans; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Kidney Transplantation - methods; Male; mammalian target of rapamycin inhibitor; metabolism; Protein Kinases - drug effects; Radioimmunoassay; rapamycin; Rats; Rats, Wistar; sirolimus; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases; Treatment Outcome
• ISSN: 0934-0874; 1432-2277
• DOI: 10.1111/j.1432-2277.2008.00710.x

Summary The aim was to study the influence of sirolimus (SRL) on body weight in a rat model and in kidney transplant patients. Wistar rats (15 weeks old) were either treated with vehicle (VEH; n = 8) or SRL (n = 7) 1.0 mg/kg three times per week for 12 weeks. Body mass and food intake were measured weekly. Adipocyte diameter was determined in hematoxylin–eosin stains. The body mass index (BMI) obtained from clinical kidney transplant trials comparing SRL‐based with cyclosporine‐based therapy was analyzed. Animals: SRL produced a decrease of the weight gain curve. At the end of the study, mean body weight in the SRL group was lower than in the VEH group (356 vs. 507 g, P < 0.01) in spite of comparable food intake normalized for body weight was not different. Mean adipocyte diameter was 36 μm in VEH and 25 μm in SRL rats (P = 0.009). Mean SRL blood trough concentration was 38 ng/ml. Kidney transplant patients: Two years after transplantation, BMI was significantly lower in the SRL‐based treatment arm compared to cyclosporine (24.17 ± 2.99 vs. 25.97 ± 5.01 kg/m2, P = 0.031). SRL treatment leads to less body mass. Adipocyte cell diameter was reduced in SRL‐treated animals. A possible explanation may be the effects of SRL on metabolic regulation and cell growth.