羟丙基-β-环糊精-氟他胺包合物。II. 氟他胺在大鼠体内的口服及静脉药代动力学

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

作者信息

Zuo Zhong, Tam Yun K, Diakur James, Wiebe Leonard I

机构信息

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.

出版信息

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

PMID:12553899

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.

摘要

目的

本研究旨在确定氟他胺（FLT）及其活性代谢物2-羟基氟他胺（FLT-2-OH）在大鼠体内的药代动力学，采用羟丙基-β-环糊精（FLT-HPBetaCyD）进行制剂研究。

方法

分别比较口服（p.o.）和静脉注射（i.v.）给药后FLT-HPBetaCyD、氟他胺混悬液（FLT-SUSP）和氟他胺溶液（FLT-COSOLV）的药代动力学。在非交叉设计中，雄性Sprague-Dawley大鼠通过灌胃接受每种制剂的单次口服剂量[15mg（54μmol）FLT/kg]，或通过颈静脉留置导管接受单次静脉注射剂量[1.6mg（5.8μmol）FLT/kg]。通过高效液相色谱法测定血浆和尿液等分试样中的FLT及其代谢物FLT-2-OH。

结果

在初步体外实验中，采用透析袋溶解法，80%的测试剂量的FLT在2小时内从冻干的FLT-HPBetaCyD释放到模拟胃液中，相比之下，市售氟他胺粉末（FLT-SUSP）的释放率不到5%。口服FLT-HPBetaCyD后，FLT的血浆浓度曲线下平均面积（AUC(0-∞)）为1580±228ng x h/mL，给药后0.5小时（Tmax）达到最大血浆浓度（Cmax；1297±127ng/mL）。AUC(0-∞)和C(max)显著高于FLT-SUSP给药后（AUC(0-∞) 748±206ng x h/mL；C(max) 230±111ng/mL和T(max) 2.33±0.29小时）。静脉注射FLT-HPBetaCyD后，FLT的AUC(0-∞)为1355±162ng x h/mL，而FLT-COSOLV为1421±283ng x h/mL。FLT的C(max)分别为714±144mL/h和735±88mL/h。各自的分布容积（V(z)）分别为369±191mL和242±25mL。FLT-HPBetaCyD和FLT-COSOLV给药后FLT的血浆浓度-时间曲线和药代动力学参数无显著差异。静脉给药后FLT-2-OH的药代动力学参数与制剂无关，但在口服研究中，FLT-HPBetaCyD的AUC(0-∞)、C(max)和T(max)值显著更高（分别为40269±5875ng x h/mL、4,062±502ng/mL和3.50±0.41小时）。