Park Y H, McCue B A, Dobbs R E, York B M, Brazzell R K
Alcon Laboratories, Inc., Fort Worth, TX 76134.
J Pharm Sci. 1988 Jul;77(7):591-5. doi: 10.1002/jps.2600770709.
Two selective high-performance liquid chromatographic (HPLC) methods have been developed for the quantitative determination of spiro-(2-fluoro-9H-fluorene-9,4'-imidazolidine)-2',5'-dione (AL01567; 1) in plasma and urine, with an assay sensitivity of 0.25 micrograms/mL for plasma and 0.13 micrograms/mL for urine. The plasma assay procedure involved precipitation of proteins with acetonitrile followed by dilution with water. The diluted supernatant was analyzed on an ODS column eluting with acetonitrile:0.5% phosphoric acid (30:70) adjusted to pH 7.2 with concentrated ammonium hydroxide. The urine assay procedure involved extraction of 1 with 10% n-butanol in hexane, followed by back extraction with 0.05 M sodium hydroxide. The basic extract was neutralized and analyzed on a phenyl column eluting with acetonitrile:10 mM potassium phosphate (30:70; monobasic, pH 5.6). The pharmacokinetics of 1 was investigated in humans following single and multiple oral doses. The elimination half-life from 12 normal subjects following single 100-400-mg oral doses was independent of dose, and the overall mean half-life was 66 +/- 9 h. The overall mean oral clearance (assuming a bioavailability of 100%) was 11 +/- 3 mL/min, and the mean apparent volume of distribution was 59 +/- 13 L. The mean urinary recovery of intact drug during the first 24 h after dosing was 1.2 +/- 0.4% of the administered dose. During once daily 100-mg oral dosing of 1 to five subjects for 21 d, plasma concentrations of 1 reached apparent steady-state by 7 d.(ABSTRACT TRUNCATED AT 250 WORDS)
已开发出两种选择性高效液相色谱（HPLC）方法，用于定量测定血浆和尿液中的螺环-(2-氟-9H-芴-9,4'-咪唑烷)-2',5'-二酮（AL01567；1），血浆检测灵敏度为0.25微克/毫升，尿液检测灵敏度为0.13微克/毫升。血浆检测程序包括用乙腈沉淀蛋白质，然后用水稀释。稀释后的上清液在ODS柱上进行分析，用乙腈:0.5%磷酸（30:70）洗脱，并用浓氢氧化铵调至pH 7.2。尿液检测程序包括用10%正丁醇的己烷溶液萃取1，然后用0.05 M氢氧化钠反萃取。碱性萃取液中和后在苯基柱上进行分析，用乙腈:10 mM磷酸钾（30:70；磷酸二氢钾，pH 5.6）洗脱。在单次和多次口服给药后，对1在人体中的药代动力学进行了研究。12名正常受试者单次口服100 - 400毫克剂量后的消除半衰期与剂量无关，总体平均半衰期为66±9小时。总体平均口服清除率（假设生物利用度为100%）为11±3毫升/分钟，平均表观分布容积为59±13升。给药后最初24小时内完整药物的平均尿回收率为给药剂量的1.2±0.4%。在对5名受试者每日口服100毫克1，持续21天的过程中，1的血浆浓度在7天时达到明显稳态。（摘要截短至250字）
