Blood and plasma pharmacokinetics of ciclosporin in diabetic kidney transplant recipients.

BACKGROUND AND OBJECTIVES: Long-term diabetes mellitus may affect the absorption, distribution and metabolism of immunosuppressive agents used after organ transplantation. The aims of this study were to characterize ciclosporin pharmacokinetics in blood and plasma and to compare the ciclosporin unbound concentration and the blood : plasma concentration (B : P) ratio in diabetic kidney transplant recipients. PATIENTS AND METHODS: Ciclosporin 12-hour steady-state pharmacokinetics were studied in eight diabetic and nine nondiabetic patients. Ciclosporin concentrations in whole blood and in plasma were measured using liquid chromatography-tandem mass spectrometry, and the ciclosporin fraction unbound (f(u)) was determined by an equilibrium dialysis method utilizing [(3)H]ciclosporin as a tracer. Oral absorption of paracetamol (acetaminophen) was used as a marker for gastric emptying.
RESULTS: In diabetic patients, the time to the peak blood ciclosporin concentration at steady state (t(max)(,ss)) was prolonged (128 minutes vs 93 minutes in nondiabetic patients, p < 0.01) and, on average, the paracetamol t(max) was prolonged by 30 minutes. The whole-blood dose-normalized area under the concentration-time curve from 0 to 12 hours (AUC(12)) was marginally lower in diabetic patients (p = 0.09) and the plasma AUC(12) was significantly lower (p = 0.03). The ciclosporin f(u) was numerically higher in diabetic patients (1.20 +/- 0.65% vs 0.72 +/- 0.28% in nondiabetic patients, p = 0.066); however, the unbound concentration values were essentially similar in the two groups (0.58 +/- 0.76 microg/L in diabetic patients and 0.52 +/- 0.48 microg/L in nondiabetic patients; p = 0.59). No difference was observed in the ciclosporin B : P ratio between the two groups.
CONCLUSION: This study indicates that diabetes delays ciclosporin absorption, reduces ciclosporin exposure and increases the ciclosporin f(u) but not the pharmacologically active unbound concentration.