Gender- and dose-related effects of cyclosporin A on hepatic and bone metabolism

Autor(en)

Walter Jäger, Huiqing Xu, Katrin Wlcek, Christiane Schüler, Franz Rubel, Reinhold G. Erben

Abstrakt

Previous data have shown gender-related differences in the skeletal effects of the immunosuppressive drug cyclosporin A (CsA) in rats. To test the hypothesis that the gender-related skeletal effects of CsA are caused by gender-specific metabolism of this drug, we treated aged male and female sham-operated, gonadectomized (GX) as well as sex hormone-supplemented GX rats with 5 mg/kg CsA three times per week for 2 months, and analyzed the bone phenotype as well as the concentrations of CsA and its major metabolites AM1, AM1c, AM9, and AM4N in blood, urine, and liver tissue. CsA treatment induced high turnover osteopenia in mates, but not females. Male rats showed several-fold higher CsA and CsA metabolite blood levels compared with females. Renal clearance data revealed that CsA undergoes selective tubular reabsorption in male, but not female rats. However, a mathematical modeling approach demonstrated that the higher CsA blood levels in males were almost exclusively caused by a 6-fold lower hepatic clearance rate compared with females. In addition, we subcutaneously treated female rats with up to 6-fold higher doses of CsA. Similar to males, high dose CsA induced high turnover osteopenia in female rats. Our data show that the gender-related differences in the skeletal effects of CsA are caused by a higher hepatic clearance rate for CsA in female compared to male rats, and not by a differential skeletal response to CsA. Moreover, our study indicates that CsA blood levels of

Organisation(en)

Externe Organisation(en)

Ludwig-Maximilians-Universität München, Veterinärmedizinische Universität Wien

Journal

Bone

Band

50

Seiten

140-148

Anzahl der Seiten

9

ISSN

8756-3282

DOI

https://doi.org/10.1016/j.bone.2011.10.005

Publikationsdatum

2012

Peer-reviewed

Ja

ÖFOS 2012

301209 Pharmazie

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/c5bd3386-f413-4f00-aed8-0bae6d598cea