Paliwal J K, Gupta R C
Pharmacokinetics and Drug Metabolism Division, Central Drug Research Institute, Lucknow, India.
Drug Metab Dispos. 1996 Feb;24(2):148-55.
This study reports assay methodology, tissue distribution, and the basic pharmacokinetic behavior of centchroman and its 7-desmethyl metabolite [7-desmethyl centchroman (DMC)] after a single 12.5 mg/kg po dose in young female rats. Plasma, liver, lung, spleen, uterus, and adipose tissue were collected at various time intervals up to 14 days after dose. Reversed-phase HPLC, coupled with fluorescence detector, was used for simultaneous determination of centchroman and DMC in biosamples. The drug and metabolite were quantitated up to 2 and 5 ng/ml in plasma and 10 and 20 ng/g in tissues, respectively. The assay method was validated in terms of accuracy, precision, interassay, and intraassay variability, and was found to be reliable and reproducible. Peak centchroman levels in all of the tissues were found between 8-12 hr, whereas DMC peaks appeared between 8 and 24 hr, except that in liver the first peak of 1.2 micrograms/g appeared in the 1-hr sample. Tissue-to-plasma concentration ratios of centchroman were > 200 times in the lung; > 100 times in the spleen, liver, and adipose tissue; and > 40 times in the uterus at maxima in each tissue. Similarly, tissue concentrations of DMC were > 350 times in the lung, > 100 times in the liver and spleen, and > 25 times in the uterus and adipose tissue than in the plasma. High tissue-to-plasma concentration ratios of metabolites than the parent drug are indicative of its greater affinity for tissues. Terminal half-life of the centchroman and DMC in plasma were 24.1 and 36.6 hr, respectively. The mean residence time of centchroman was highest in the liver (78.4 hr), followed by the uterus (72.7 hr), adipose tissue (47.5 hr), lung (46 hr), spleen (44.1 hr), and plasma (37.7 hr). The mean residence time of DMC was also highest in the liver (133.7 hr), followed by the uterus (122 hr), adipose tissue (85.2 hr), lung (62.6 hr), spleen (62.6 hr), and plasma (48.2 hr).
本研究报告了在年轻雌性大鼠中单次口服12.5mg/kg剂量后，炔诺酮及其7-去甲基代谢物[7-去甲基炔诺酮（DMC）]的分析方法、组织分布和基本药代动力学行为。在给药后长达14天的不同时间间隔收集血浆、肝脏、肺、脾脏、子宫和脂肪组织。采用反相高效液相色谱法结合荧光检测器，同时测定生物样品中的炔诺酮和DMC。药物和代谢物在血浆中的定量上限分别为2ng/ml和5ng/ml，在组织中的定量上限分别为10ng/g和20ng/g。该分析方法在准确性、精密度、批间和批内变异性方面得到了验证，结果可靠且可重复。所有组织中炔诺酮的峰值水平出现在8-12小时之间，而DMC的峰值出现在8-2小时之间，但在肝脏中，1小时样品中出现了第一个峰值，为1.2μg/g。炔诺酮在各组织中的组织-血浆浓度比在肺中>200倍；在脾脏、肝脏和脂肪组织中>100倍；在子宫中最大值时>40倍。同样，DMC在肺中的组织浓度比血浆中>350倍，在肝脏和脾脏中>100倍，在子宫和脂肪组织中>25倍。代谢物的组织-血浆浓度比高于母体药物，表明其对组织的亲和力更高。炔诺酮和DMC在血浆中的末端半衰期分别为24.1小时和36.6小时。炔诺酮的平均驻留时间在肝脏中最高（78.4小时），其次是子宫（72.7小时）、脂肪组织（%小时）、肺（46小时）、脾脏（44.1小时）和血浆（37.7小时）。DMC的平均驻留时间在肝脏中也最高（133.7小时），其次是子宫（122小时）、脂肪组织（85.2小时）、肺（62.6小时）、脾脏（62.6小时）和血浆（48.2小时）。
