萘哌地尔在家犬体内的药动学

目的 建立家犬血浆中萘哌地尔浓度的高效液相色谱分析方法,研究萘哌地尔普通片和缓释片在家犬体内的药动学规律。方法 采用内标法,以Shim-Pack ODS C18柱为固定相,甲醇-乙腈-0.02 mol·L-1磷酸二氢钾(25:25:50)为流动相,维拉帕米为内标,检测波长为240 nm,流速为0.8 mL·min-1,柱温30℃,血药浓度一时间数据采用3P97程序处理并计算药动学参数。结果 血浆中内源性物质对萘哌地尔与维拉帕米均无干扰,萘哌地尔与内标的峰面积之比同萘哌地尔浓度间有良好的线性关系,线性范围为13.6-868 ng·mL-1,最低定量浓度为13.6 ng·mL-1,方法回收率和提取回收率分别为101.2％±7.8％(n=3)、74.6％±3.6％(n=3),日内RSD≤6.9％,日间RSD≤8.4％;家犬口服100 mg萘哌地尔普通片与缓释片后,血药浓度时间曲线符合一室模型,Cmax分别为(635.1±129.8)、(63.7±163.1)ng·mL-1,tmax分别为(1.28±0.57)、(6.67±1.63)h,AUC0-t分别为(3 562±1 265)、(3 297±937)ng·mL-1·h,T1/2(Ke)分别为(3.35±0.68)、(4.01±3.14)h。结论 所建立的血浆中萘哌地尔浓度测定方法灵敏、准确,能较好地满足萘哌地尔药动学研究的需要;萘哌地尔缓释片具有明显的缓释特征。     

萘哌地尔缓释胶囊在家犬体内的药动学

目的 :研究萘哌地尔缓释胶囊在家犬体内的药动学与生物利用度。方法 :以健康家犬5只为对象 ,采用自身对照方式 ,单剂量分别给予萘哌地尔普通胶囊和缓释胶囊200mg ,血药浓度以高效液相色谱法测定。统计比较普通胶囊与缓释胶囊的生物利用度和药动学参数的差异。结果 :给药后 ,血药浓度变化符合一室模型 ,T1/2 分别为 (3 2±1 1)h、(5 9±0 8)h。普通胶囊的AUC0～∞、Cmax和Tmax 分别为 (3728 1±573 1) (ng·h)/ml、(697 5±94 2)ng/ml和 (1 2±0 59)h ;缓释胶囊的AUC0～∞、Cmax 和Tmax 分别为 (5518 3±391 1) (ng·h)/ml、(468 6±61 3)ng/ml和 (4 0±0 7)h。以普通胶囊为参比制剂 ,缓释胶囊的生物利用度为(149 8±14 4) %。结论 :萘哌地尔缓释胶囊在家犬体内表现出较好的缓释特性 ,其生物利用度明显高于普通胶囊。     

吲达帕胺在高血压患者体内药动学研究

目的研究高血压患者和健康受试者口服吲达帕胺片后体内药动学参数的差异。方法采用高效液相色谱法测定给药后不同时间点的全血中吲达帕胺浓度,依据血药浓度对房室模型进行判别。结果与健康受试者相比,高血压患者的AUC、Cmax及Tmax等参数无统计学差异,而t1/2β与MRT(0-t)显著降低(P<0.01),CL/F显著增高(P<0.01)。结论吲达帕胺在高血压患者和健康受试者体内药物动力学过程有着明显的不同,能为吲达帕胺临床合理用药提供更为全面的理论依据。     

药动学-药效学结合模型的研究进展

本主要对近年来药动学．药效学结合模型在模型建立、药理学、毒理学、临床应用及新药研发等方面的进展进行了综述，并展望其发展前景。     

莫达非尼在小鼠体内的药动学-药效学联合研究

对莫达非尼 (modafinil, MOD) 在小鼠体内的药动学和药效学进行联合研究, 以阐明其关联性, 为临床合理用药提供依据。以莫达非尼120 mg·kg⁻¹对小鼠灌胃给药, 采集给药后不同时间点血浆样本, 用HPLC检测血浆药物浓度, 分析平均血药浓度经时变化并计算药动学参数。以小鼠自主活动计数为药效学指标, 观测MOD 120 mg·kg⁻¹灌胃给药后不同时间段内小鼠自主活动量 (计数) 的变化, 分析与血浆药物浓度变化的相关性。结果显示, MOD在小鼠体内药动学过程符合二室模型, t_1/2α, t_1/2β, t_max, C_max, AUC_0−∞分别为0.42 h, 3.10 h, 1.00 h, 41.34 mg·L⁻¹和142.22 mg·L⁻¹·h。MOD使小鼠自主活动明显增多, 持续约4 h, 且与血浆药物浓度呈同步变化, 二者间存在明显的相关性。     

吲达帕胺在高血压患者体内药动学的研究

目的建立测定人全血中吲达帕胺(IND)药物浓度的HPLC-UV法,研究高血压患者和健康受试者口服(po)IND片后体内药动学参数的差异。方法 8例高血压患者及8例健康自愿者po IND片5 mg,采用HPLC-UV法(Luna C18色谱柱,pH4磷酸盐缓冲液-乙腈-甲醇(55∶40∶5)与甲醇梯度洗脱,240nm波长检测)测定给药后不同时间点的全血中IND浓度,采用DAS 2.3程序软件对血药浓度数据进行房室模型的判别,选择最佳权重、最佳房室模型。根据确定的最佳权重和房室模型求出药物动力学参数。结果受试者po IND片后的药动学过程符合权重为1的二室模型,以一级动力学方式消除。与健康受试者相比,高血压患者的AUC、Cmax及Tmax无统计学意义,而t1/2β与MRT(0-t)显著降低,CL/F显著增高。结论建立的全血中IND药物浓度的HPLC-UV测定法专属性强灵敏度适宜,IND在高血压患者和健康受试者体内药物动力学过程有着明显的不同;研究IND在高血压患者体内的药物动力学过程,能为IND临床合理用药提供更为全面的理论依据。     

尼索地平控释贴剂在自发性高血压大鼠体内的药动学-药效学结合模型的建立

目的:建立尼索地平控释贴剂(NCRP)在自发性高血压大鼠(SHR)体内的药动学-药效学(PK-PD)结合模型。方法:将SHR随机分为贴剂(NCRP)组和片剂(尼索地平片)组,每组6只,植入微透析探针,按尼索地平计每只给药5 mg。收集给药后36 h内的血浆微透析液,采用高效液相色谱法测定尼索地平血药浓度,Win Nonlin 5.3软件计算药动学参数,以心率和血压为药效学指标,进行PK-PD结合模型研究。结果:与尼索地平片比较,NCRP具有控释效果;NCRP药物效应与效应室浓度以Sigmoid-Emax模型拟合,心率和收缩压的PK-PD模型主要参数分别为Emax:(2.65±0.06)、(10.71±0.87),EC50:(83.65±35.25)、(1.29±0.26)ng/ml,γ:(0.83±0.91)、(1.2±0.35),Keo:(0.37±0.53)、(0.91±0.24)h-1。结论:成功建立了NCRP在SHR体内的PK-PD结合模型。     

萘哌地尔在大鼠体内的药代动力学

为全面了解萘哌地尔(Naf)在大鼠体内的代谢过程,用反相HPLC-UV法,给大鼠ig10,20,30mg·kg^-1Naf后,测定在不同时间各组织和体液中Naf的含量。结果表明,Naf在大鼠体内药代动力学为二室模型,T_1/2α为0.47～1.01h,T_1/2β为4.78～7.08h,达峰时间T(peak)为0.42～0.90h,Cmax,AUC随剂量升高而增大。给药后15min,肠壁组织浓度最高,其次为肝、肺;2h以后,除睾丸、卵巢和子宫外,其余组织药物浓度逐渐降低。尿、粪及胆汁中原形药总排出量不足给药量的1%,提示Naf在大鼠体内有首过效应及代谢物生成。在100～500mg·ml^-1浓度范围内,Naf血浆蛋白结合率为82%～97%。     

家兔体内呋喃苯胺酸的药动学和药效学结合模型

用药动学-药效学结合模型对呋喃苯胺酸在家兔体内的处置和效应动力学作定量分析。呋喃苯胺酸的k_(eo),S,E_(max),EC_(50)分别为0.131±0.029min~(-1),2.21±0.61,6.5±0.6ml/min,3.49±0.77μg/ml。结果表明血浆与作用部位属于不同的房室,两者之间存在着一个平衡过程。     

Pharmacokinetics and pharmacodynamics of enalapril in patients with congestive heart failure and patients with hypertension

The clinical pharmacokinetics and pharmacodynamics of enalapril and its de-esterified active metabolite, MK 422, were determined in eight patients with congestive cardiomyopathy and five patients with hypertension. After administration of single doses of 2.5, 5, and 10 mg enalapril in the congestive heart failure patients and 20 or 40 mg in the hypertensive patients, serum levels and urine elimination of enalapril and MK 422 were determined. Standing and supine heart rate and blood pressure were measured as was ejection fraction in the congestive heart failure group and renin activity, aldosterone levels, and converting enzyme activity in the hypertensive group. Apparent oral clearance after administration of 5 and 10 mg enalapril was lower in the congestive heart failure patients (0.6 +/- 0.2 and 0.7 +/- 0.4 L/min) than after 20 and 40 mg given to hypertensive patients (2.5 +/- 1.3 and 2.7 +/- 2.7 L/min). The elimination of MK 422 was also slower in the congestive heart failure patients (7.8 +/- 5.0 and 6.8 +/- 2.5 h after 5 and 10 mg enalapril, respectively, vs. 4.6 +/- 2.0 and 5.3 +/- 1.1 h after 20 and 40 mg, respectively, in the hypertension group). The enalapril area under the concentration-time curve increased disproportionately to dose increments in both groups, but was more pronounced in congestive heart failure. Twenty and 40 mg enalapril lowered the blood pressure by 2 h after dosing in the hypertension group, and peak effects were seen 4-5 h after dosing. Peak effects correlated with peak serum MK 422 concentrations but not with enalapril (MK 421) levels. Supine heart rates were unchanged after 20 mg, but increased after 40 mg; standing heart rates were transiently increased after 20 and 40 mg enalapril. Blood pressure was not significantly changed in the congestive heart failure group, and cardiac ejection fraction was unchanged. In the hypertension group, renin stimulation and converting enzyme activity inhibition were seen at 4 h and persisted for at least 24 h after administration of 40 mg enalapril. In summary, the clearance of enalapril and elimination of MK 422 was slower in congestive heart failure patients versus hypertensive patients. Therefore, slower onset and longer duration of drug effect might be anticipated in patients with congestive heart failure versus patients with hypertension during enalapril administration.     

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension

Summary Mean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 — 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r=0.80, p<0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the -blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r=0.79, p<0.001).     

Pharmacokinetics and pharmacodynamics of famotidine in patients with reflux oesophagitis

Summary The pharmacokinetics, pharmacodynamic effect and clinical efficacy of famotidine were studied in 10 patients with reflux oesophagitis Grades I and II. For the pharmacokinetic studies the patients received 20 mg famotidine i. v.The half-life of famotidine was 3.8 h, the total plasma clearance was 297 ml·min^–1, and a steady state volume of distribution of 1.21·kg^–1 was found. For pharmacodynamic assessment, intraoesophageal pH-metry was performed without and after acute treatment with famotidine 20 mg i. v. and following 3 weeks of oral famotidine 80 mg b. d. The resultant percentage total acid exposure time (pH<4 within 24 h) were 23.9%, 19.0% and 19.2% (median), respectively (NS). At the end of 6 weeks of oral therapy, symptomatic and endoscopic improvement had occurred in 9 and 5 patients, respectively.Our study shows that the pharmacokinetics of famotidine in patients with reflux oesophagitis is comparable to that in healthy volunteers and peptic ulcer patients. The clinical response to the treatment appeared comparable to that found after other H₂-receptor antagonists.     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

Pharmacokinetics,pharmacodynamics and safety of a single-dose long-acting Risperidone injection in Chinese patients with schizophrenia

In the present study, we aimed to determine the pharmacokinetics (PK), pharmacodynamics (PD), adverse events (AEs), and their relationships in Chinese patients with schizophrenia after a single dose of long-acting risperidone. Schizophrenic patients (six females and seven males) were enrolled in this study. Serial blood samples were collected after drug administration during 63 d, and the drug concentrations were analyzed by LC-MS/MS. Safety and tolerance were evaluated by monitoring the AEs, changes in clinical laboratory results, 12-lead ECG, vital signs, physical examination, and injection-site reactions. The extrapyramidal symptoms were evaluated using the ESRS. Efficacy was evaluated by the PANSS and BPRS. Twelve out of the 13 participants completed the trial. There were few clinically meaningful changes in mean clinical laboratory values, vital signs, or ECG parameters, except for the prolactin level and body weight. There were no serious AEs, and those observed were reversible. Significant clinical improvements in PANSS and PANSS-derived BPRS total scores were observed. The mean (standard deviation, coefficient of variation) values for these PK parameters were as follows: C_max, 8.954 (8.059, 90.0%) ng/mL; area under the curve AUC_0–t, 2453 (1156, 47.1%) ng?h/mL; AUC_0–∞, 2472 (1160, 46.9%) ng?h/mL; t_max, 830.0 (min: 744.0, max: 984.0, 11.8%) h; and t_1/2, 68.56 (10.77, 15.7%) h. The PK characteristics of long-acting risperidone showed a high level of inter-individual variation, while there were no clear correlations between PK, efficacy and AEs among the patients in the present study.     

Pharmacokinetics and pharmacodynamics of vildagliptin in healthy Chinese volunteers

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.     

Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria

Summary We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o.The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients.Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42 %. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients.In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.     

Pharmacokinetics and pharmacodynamics of roxatidine in patients with renal insufficiency.

1. Roxatidine acetate, a new histamine H2-receptor antagonist, was administered in the evening (75 mg p.o.) to eight patients with renal insufficiency (CLCR 8-17 ml min-1) for 12 days and plasma drug concentrations were measured. 2. Ambulatory intragastric pH was monitored following the last dose and values were compared with those on day 1 when all patients received a placebo. 3. The terminal elimination half-life (mean +/- s.d.) of roxatidine was 10.8 +/- 2.4 h and its oral clearance was 178 +/- 43 ml min-1. 4. During roxatidine treatment gastrin levels increased slightly (median 189 vs 289 ng l-1) and the hyperparathyroid status of the patients was almost normalized (parathyroid hormone levels: median 199 vs 132 ng l-1). 5. The mean latency to a gastric pH of at least 4 was 4.3 +/- 1.4 h. The duration of action (intragastric pH > 4) was 10.6 +/- 3.9 h. 6. As in a pilot study with six patients (CLCR < or = 17 ml min-1) the recommended dosage regimen (75 mg 48 h-1) was unable to maintain gastric pH > 4 for more than 6 h, daily nocturnal intake of 75 mg roxatidine acetate appears appropriate to elevate gastric pH > 4 for a sufficient period of time.     

Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer.

Topotecan, a semisynthetic water-soluble analog of camptothecin, is the first topoisomerase I-directed drug to enter clinical trial in the United States in over 20 yr. In this study, 30-min infusions of topotecan were administered daily for 5 days every 3 weeks at doses ranging from 0.5 to 2.5 mg/m2. Topotecan is reversibly hydrolyzed in a pH-dependent reaction in aqueous solutions to the ring-open hydroxy acid. The disposition of the closed ring lactone has been studied in 26 patients, and the disposition of both lactone and hydroxy acid has been studied in 12 patients. The clearance rate for topotecan lactone was 1220 ml/min/m2, with a range of 300-4760 ml/min/m2. The clearance rate for total topotecan (lactone and hydroxy acid) was 493 ml/min/m2, with a range of 163-815 ml/min/m2. A model for the disposition of lactone and hydroxy acid incorporating both reversible hydrolysis and elimination was developed. We have shown that topotecan is partially hydrolyzed prior to administration in parenteral solutions, and that clearance of the parent compound proceeds in vivo by conversion to hydroxy acid and elimination. Renal clearance accounted for 30 +/- 18% of drug elimination in patients. The relationship between topotecan dose and myelotoxicity is well fit by a sigmoidal Emax model, as is the relationship between total topotecan area under the concentration-time curve and myelotoxicity. The disposition of topotecan was also studied in mice. The clearance rate for total topotecan in mice was 330 ml/min/m2 after administration of topotecan lactone.(ABSTRACT TRUNCATED AT 250 WORDS)