Hydroxypropyl-beta-cyclodextrin-flutamide inclusion complex. II. Oral and intravenous pharmacokinetics of flutamide in the rat

J Pharm Pharm Sci. Sep-Dec 2002;5(3):292-8.


Purpose: The objective of this work was to determine the pharmacokinetics of flutamide (FLT) and its active metabolite, 2-hydroxy-flutamide (FLT-2-OH) in rats, following formulation in hydroxypropyl-Beta-cyclodextrin (FLT-HPBetaCyD).

Methods: The pharmacokinetics of FLT-HPBetaCyD, FLT-suspension (FLT-SUSP), and FLT-solution (FLT-COSOLV) were compared after oral (p.o.) and intravenous (i.v.) administration, respectively. In a non-crossover design, male Sprague-Dawley rats received each formulation as a single oral dose [15 mg (54 micro mol) FLT/kg] by oral gavage, or single i.v. dose [1.6 mg (5.8 micro mol) FLT/kg] via an indwelling jugular vein catheter. FLT and its metabolite, FLT-2-OH, were determined in plasma and urine aliquots by an HPLC method.

Results: In a preliminary in vitro experiment, using the dialysis bag dissolution method, 80% of a test dose of FLT was released from lyophilized FLT-HPBetaCyD into simulated gastric juice within 2 h, compared to less than 5% release from commercial FLT powder (FLT-SUSP). Following oral FLT-HPBetaCyD, the mean area under the plasma concentration curve (AUC(0- infinity)) for FLT, was 1580 +/- 228 ng x h/mL, with the maximum plasma concentration (Cmax; 1297 +/- 127 ng/mL) at 0.5 h (Tmax) after administration. The AUC(0- infinity) and C(max) were significantly higher than after FLT-SUSP (AUC(0- infinity) 748 +/- 206 ng x h/mL; C(max) 230 +/- 111 ng/mL and T(max) 2.33 +/- 0.29 h, respectively). After i.v. FLT-HPBetaCyD, the FLT AUC(0- infinity) was 1355 +/- 162 ng x h/mL, compared to 1421 +/- 283 ng x h/mL for FLT-COSOLV. FLT C(max) were 714 +/- 144 mL/h and 735 +/- 88 mL/h, respectively. The respective volumes of distribution (V(z)) were 369 +/- 191 mL and 242 +/- 25 mL. The plasma concentration-time profile and pharmacokinetic parameters of FLT after FLT-HPBetaCyD and FLT-COSOLV did not differ significantly. The pharmacokinetic parameters for FLT-2-OH were formulation independent after i.v. dosing, but AUC(0- infinity); C(max) and T(max), values were substantially greater with the FLT-HPBetaCyD in the oral study (40269 +/- 5875 ng x h/mL, 4062 +/- 502 ng/mL, and 3.50 +/- 0.41 h, respectively).

Conclusions: FLT from FLT-HPBetaCyD was released rapidly into solution in vitro and in vivo. FLT-HPBetaCyD improved oral bioavailability relative to FLT-SUSP. Intravenous pharmacokinetic profiles for both FLT and FLT-2-OH were identical following either FLT-HPBetaCyD or FLT-COSOLV, indicating that the FLT-HPBetaCyD formulation behaved as a true solution.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Administration, Oral
  • Animals
  • Area Under Curve
  • Biological Availability
  • Cyclodextrins / administration & dosage*
  • Cyclodextrins / blood
  • Cyclodextrins / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Flutamide / administration & dosage*
  • Flutamide / blood
  • Flutamide / pharmacokinetics*
  • Infusions, Intravenous
  • Male
  • Metabolic Clearance Rate
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Time Factors
  • beta-Cyclodextrins*


  • Cyclodextrins
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Flutamide