Hydroxypropyl-beta-cyclodextrin-flutamide inclusion complex. II. Oral and intravenous pharmacokinetics of flutamide in the rat.
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".