Background: Tacrolimus (TAC), an important immunosuppressant for liver transplantation, has a narrow therapeutic index and large individual differences in pharmacokinetics. Ascitic fluid is commonly drained after liver transplantation. However, the distribution of TAC in ascitic fluid and the influence of drained ascitic fluid on whole-blood TAC are unclear. Methods: The ascitic fluid samples from twenty liver transplant recipients who were received TAC treatment within 12h after the transplantation surgery were collected for consecutive 24h in different days after the surgery. The distribution of TAC in ascitic fluid were evaluated by using a sensitive UPLC-MS/MS method. Chromatographic separation was achieved on an Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column (2.1×100mm, 3.5μm). Mass spectrometry was performed in multiple reaction monitoring (MRM) conditions of transitions m/z 821.4→768.5 for TAC. Results: The concentrations of TAC in ascitic fluid samples range from 0.2 to 3.0 ng/mL, accounting for 1.19-31.87% of whole-blood TAC concentrations. A linear mixed model showed a statistically significant positive correlation between the steady-state trough blood concentration of TAC (C0) and the corresponding amount of TAC excreted in the ascitic fluid for 24 consecutive hours, especially after normalization by the daily dose per unit body weight (D/W). Conclusions: These data suggested that the distribution of TAC in ascitic fluid has great individual differences. The whole-blood TAC concentration, D/W and other confounding factors may contribute to the excretion of TAC in ascitic fluid, but the influence of TAC excretion in drained ascitic fluid on the whole-blood TAC concentration is negligible.

Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR2285, the first oral coagulation factor XIa (FXIa) inhibitor developed in China in combination with aspirin, clopidogrel or ticagrelor in healthy subjects. Methods: This study was a single-center, randomized, double-blind, placebo-controlled (only SHR2285) design. A total of 52 healthy subjects, 29 male and 23 female, were enrolled in this study. The subjects were divided into three groups: A, B and C, 16 subjects in group A (aspirin+clopidogrel+placebo or SHR2285 200mg bid (1:3)), 16 subjects in group B (aspirin+clopidogrel+placebo or SHR2285 300mg bid (1:3)) and 20 subjects in group C (aspirin+ticagrelor+placebo or SHR2285 300mg bid (2:3)), respectively. All groups were administered orally for 6 consecutive days. Results: 1. SHR2285 was well tolerated, and all adverse events were mild. There was no evidence of an increased risk of bleeding. 2. After 6 days of twice-daily administration, SHR2285 could reach a steady state. The half-life of SHR2285 was 13.9h, 14.5h and 13.8h respectively. 3. SHR2285 markedly inhibited FXI: C and prolonged APTT. The maximum inhibition rates of FXI: C in the three groups were 84.8%, 89.3% and 92.2% and the maximum prolongation time of APTT was 2.08-, 2.36-, and 2.26-fold, respectively. 4. The combination of aspirin, clopidogrel or ticagrelor had limited effect on the AUC of SHR2285. Conclusion: These data suggest that SHR2285, a potential oral FXIa inhibitor, is expected to become a novel, safe and effective anticoagulant.