The effect of therapeutic doses of cyclosporine A (CyA) on bile flow and bile salt output was studied in the rat. Thirty male Sprague-Dawley rats (250 to 380 g) were injected intraperitoneally with CyA (n = 15) or vehicle (n = 15) at the dose of 10 mg.kg-1 for 3 weeks. The effect of CyA on basal and taurocholate-induced bile flow, on basal bile salt output and bile salt output under taurocholate infusion, and the effect of chronic administration of CyA on bile salt-independent bile flow was evaluated. Administration of CyA was associated with a decrease in basal bile flow (5.6 +/- 0.7 vs 6.7 +/- 0.7 microliters.min-1.100 g-1; p less than 0.001) and bile flow under taurocholate infusion (8.0 +/- 0.8 vs 10.9 +/- 1.1 microliters.min-1.100 g-1; p less than 0.001). Basal bile salt output (133.9 +/- 48.2 vs 173.8 +/- 53.6 nmol.min-1.100 g-1; p less than 0.003) and bile salt output under the infusion of taurocholate were significantly lower in cyclosporine-treated rats than in controls (443.3 +/- 48.2 vs 617.2 +/- 172.7 nmol.min-1.100 g-1; p less than 0.001). There was no significant difference in bile salt-independent bile flow between the 2 groups. There was no modification of seric alanine aminotransferase activity or hepatic histology. This study confirms that chronic administration of CyA at therapeutic doses can induce cholestasis. Cholestasis is related mainly to a decrease in bile salt secretion and bile salt-dependent flow.