UCN-01 (U) is a potent inhibitor of cell cycle progression now being investigated as an antitumor agent. Preclinical studies have demonstrated significant (>95%) plasma protein binding (PPB) of U, especially to the α1-acidic-glycoprotein (AAG) fraction. Patients (n=14) enrolled in a Phase I trial of UCN-01 + cytarabine at our institution experienced unexpected cardiopulmonary toxicity. In order to assess the variability and role of drug binding in this toxicity we examined, in vitro, the effects of both albumin (Alb) and AAG on U PPB. Equilibrium dialysis techniques were used to measure the free fraction of U in the presence of varying ratios of Alb and AAG. Artificial plasma, spiked with UCN-01, was dialyzed for 36-hours @ 37°C against a Sorensen's solution using cellulose membranes with a MW cutoff of 12-14KD. Results (below) suggest while Alb and AAG play a role in UCN-01 PPB, AAG is more important. Varying AAG concentration resulted in the largest changes in UCN-01 free fraction. Mean Percent UCN-01 Alb Alb Alb Protein STD 3g/dL 4g/dL 5g/dL Bound (%) (%) AAG 50 mg/dL 85.26 88.52 89.24 87.67 2.12 AAG 100 mg/dL 90.35 92.44 91.63 91.47 1.05 AAG 200 mg/dL 97.94 97.81 96.6 97.45 0.74 AAG 300mg/dL 99.69 99.82 100 99.84 0.16 With a mean PPB in human subjects of 97%, these data demonstrate that slight variations in plasma AAG concentration would result in large variations in free drug exposure.
|Original language||English (US)|
|Journal||Clinical Pharmacology and Therapeutics|
|State||Published - Dec 1 2001|
ASJC Scopus subject areas
- Pharmacology (medical)