Concurrent with a phase-II trial of 4HPR in patients with various
cancers, we studied the plasma pharmacokinetics of both 4HPR and its major metabolite
4MPR as well as the effect of 4HPR administration on plasma
retinol concentrations using a simple, specific and sensitive HPLC procedure. Initial estimates of plasma pharmacokinetic parameters after
oral administration of 4HPR (300 mg/day) [corrected] in 3
cancer patients were the following: 4HPR, t beta 1/2 = 13.7 hr, AUC = 3.49 micrograms.hr/ml, CL = 56.57 L/hr/m2;
4MPR, t beta 1/2 = 23.0 hr, AUC = 1.15 micrograms.hr/ml, CL = 239.29 L/hr/m2. We also found that
oral administration of 4HPR resulted in a rapid, profound and significant reduction in plasma
retinol concentrations. The mean plasma
retinol concentrations for 9 patients decreased 60% from baseline to below 200 ng/ml within 1-2 weeks of 4HPR dosing initiation. In addition, there was a concurrent, significant reduction in plasma
retinol-binding protein levels in these patients. The mechanism whereby 4HPR reduces plasma
retinol levels in vivo has not been determined. The addition of 4HPR to pooled human plasma at 37 degrees C in vitro did not reduce endogenous
retinol levels, suggesting no direct chemical interaction between these 2
retinoids.