Ursodeoxycholic acid modulates cyclosporin A oral absorption in liver transplant recipients

The aim was to study the ursodeoxycholic acid (UDC) effect on thr cyclospor in A (CsA) pharmacokinetics after oral administration of the microemulsion Formulation Neoral(R) (CsA-ME) in liver transplant recipients, and test the potential protective effect of this bile acid on liver and renal CsA-ME-in duced toxicity. At entry into the study, 12 patients who underwent orthotop ic liver transplantation received CsA-ME. for at least 6 months. They then received a cotreatment CsA-ME plus UDC (13.8 mg.kg (1).day(-1)) for three m onths. Blood concentrations of CsA were measured using a monoclonal antibod y specific For the parent compound. The kinetic data were analysed by a mat hematical model incorporating a time dependent rate coefficient for CsA int estinal absorption, before and after UDC treatment. Changes in serum marker s of hepatic and renal injury were assessed. Individual serum bile acids we re determined by chromatography. Serum levels of UDC increased from 3 to ab out 45 % of total serum bile acids after UDC treatment. The estimated model parameters indicate that UDC administration modulates CsA intestinal absor ption. In the nine non-cholestatic patients, UDC reduced the absorption lat e and the bioavailability of CsA without modifying the elimination rate con stant of CsA and the CsA pre-drug levels. In contrast, in the three cholest atic patients, the bioavailability tended to be higher and the absorption r ate faster when CsA was combined with UDC. UDC significantly decreased elev ated gamma -glutamyl transferase and creatinine serum levels and induced so me clinical improvements such as disappearance of headaches in four patient s. In conclusion, a 3-month UDC treatment modifies CsA intestinal absorptio n without affecting CsA elimination rate constant. On the other hand, UDC s upplementation appears to improve CsA tolerability. (C) 2000 Editions scien tifiques et medicales Elsevier SAS.