Verho M, Luck C, Stelter W J, Rangoonwala B, Bender N
Hoechst AG, Frankfurt am Main, Germany.
Curr Med Res Opin. 1995;13(5):264-73. doi: 10.1185/03007999509111551.
In order to evaluate the pharmacokinetics and excretion of ramipril in man, 8 cholecystectomy patients aged between 53 and 68 years received 5 mg ramipril orally as a single dose. All patients had a T-drain inserted to permit bile collection; all gave their informed consent to participate in the trial. Serum samples were collected half-hourly until 2 hours, then hourly until 6 hours, then at 8, 10, 24 and 25 hours after intake. Urine was collected in 2-hour fractions until 8 hours, followed by a 4- and a 12-hour fraction. Bile was collected hourly until 6 hours, followed by a 6- and a 12-hour collecting fraction. Concentrations of ramipril and ramiprilat in serum, and determinations in urine and bile of ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine and diketopiperazine acid were made; total amounts excreted were calculated. Peak concentrations of ramiprilat in plasma (8.7 +/- 1.6 ng/ml) were reached after about 8 hours. AUC0-8 and AUC0-24-values were 36.5 and 111.9 ng.h/ml, respectively. Ramiprilat Cmax-concentrations were about 300-fold higher in bile than in plasma, the corresponding difference for ramipril between bile and plasma was about 4-fold. The main fractions excreted in the urine were diketopiperazine acid and ramiprilat amounting to 13.2 +/- 5.6 and 4.4 +/- 2.4%, respectively, of the dose administered. Only a very small fraction of the dose was excreted with urine as unchanged ramipril, on average 0.9 +/- 1.0%. The main fractions excreted in the bile were diketopiperazine acid, ramiprilat glucuronide and diketopiperazine, 9.0 +/- 5.3, 3.4 +/- 4.2 and 2.0 +/- 1.2% in 24 hours, respectively, of the dose administered. Only a negligible fraction of the dose (average 0.1 +/- 0.1%) was excreted with bile as unchanged ramipril. In conclusion, there is strong evidence that circulating ramipril and ramiprilat are eliminated by both the liver and the kidneys. For the patients studied it can be estimated from late collection periods that some 2/3 of circulating ramipril and ramiprilat are eliminated by the kidneys and 1/3 eliminated by the liver.
为评估雷米普利在人体内的药代动力学及排泄情况，8名年龄在53至68岁之间的胆囊切除患者口服5毫克雷米普利单剂量药物。所有患者均插入T型引流管以收集胆汁；所有患者均已签署知情同意书参与试验。服药后半小时至2小时每半小时采集一次血清样本，之后至6小时每小时采集一次，然后在8、10、24和25小时采集。尿液按2小时分段收集至8小时，随后收集4小时和12小时的尿液。胆汁每小时收集至6小时，随后收集6小时和12小时的胆汁。检测血清中雷米普利和雷米普利拉的浓度，以及尿液和胆汁中雷米普利、雷米普利拉、雷米普利葡萄糖醛酸苷、雷米普利拉葡萄糖醛酸苷、二酮哌嗪和二酮哌嗪酸的含量；计算排泄总量。血浆中雷米普利拉的峰值浓度（8.7±1.6纳克/毫升）约在8小时后达到。AUC0 - 8和AUC0 - 24值分别为36.5和111.9纳克·时/毫升。胆汁中雷米普利拉的Cmax浓度比血浆中高约300倍，胆汁与血浆中雷米普利的相应差异约为4倍。尿液中排泄的主要成分是二酮哌嗪酸和雷米普利拉，分别占给药剂量的13.2±5.6%和4.4±2.4%。以未改变的雷米普利形式经尿液排泄的剂量仅占极小部分，平均为0.9±1.0%。胆汁中排泄的主要成分是二酮哌嗪酸、雷米普利拉葡萄糖醛酸苷和二酮哌嗪，24小时内分别占给药剂量的9.0±5.3%、3.4±4.2%和2.0±1.2%。以未改变的雷米普利形式经胆汁排泄的剂量仅占可忽略不计的部分（平均0.1±0.1%）。总之，有充分证据表明循环中的雷米普利和雷米普利拉可通过肝脏和肾脏消除。对于所研究的患者，从后期收集阶段可估计出，循环中的雷米普利和雷米普利拉约2/3经肾脏消除，1/3经肝脏消除。
