Variable effect of ursodeoxycholic acid on cyclosporin absorption after orthotopic liver transplantation

The acute effects of administering a single dose of ursodeoxycholic acid (UDCA) on cyclosporin pharmacokinetics were recorded during paired studies in twelve liver transplant recipients, six of whom were cholestatic. Cyclosporin was measured using monoclonal selective antibodies (for parent drug) and non-selective antibodies (for cyclosporin plus metabolites). UDCA resulted in more rapid absorption of cyclosporin in 8 of 12 cases (67%) but had no effect in two patients with and two patients without cholestasis. Median tmax did not change significantly after UDCA (3.0 vs 4.0 h without UDCA) and only 7 of 12 patients (58%) showed a rise in the amount of cyclosporin absorbed over 24 h with the AUC not having changed significantly (median 4527 vs 4979 micrograms.h.l-1 without UDCA). Median Cmax and C24 also increased only marginally following UDCA administration (616 vs 587 micrograms.l-1 and 87 vs 58 micrograms.l-1 without UDCA, respectively). In the cholestatic patients, median AUC was 50% smaller (3223 vs 6439 micrograms.h.l-1) and median t1/2 a was 100% longer (1.58 vs 0.8 h) than in patients without cholestasis. There was no consistent improvement in cyclosporin pharmacokinetics in the cholestatic patients following UDCA, although the significantly elevated ratio of non-selective:selective AUC measurements (median 4.8 vs 2.7) fell markedly in the two most severely affected, possibly as a result of an increased clearance of cyclosporin metabolites by choleresis.