Blood and Plasma Pharmacokinetics of Ciclosporin 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 [³H]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 (AUC₁₂) was marginally lower in diabetic patients (p = 0.09) and the plasma AUC₁₂ was significantly lower (p = 0.03). The ciclosporin fu 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 μg/L in diabetic patients and 0.52 ± 0.48 μg/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.