穿琥宁肠溶胶囊在犬体内的药物动力学及绝对生物利用度

目的　研究穿琥宁肠溶胶囊在犬体内的药物动力学及绝对生物利用度。方法　家犬 6只 ,随机分为 2组 ,采用单剂量交叉给药方案 ,分别给犬单剂量静脉注射或口服穿琥宁肠溶胶囊 ,用HPLC法测定给药后的血中药物浓度 ,3p97药动学程序处理。结果　穿琥宁肠溶胶囊的药 -时数据符合二室模型 ,Cmax为 2 4 .3μg·ml-1,Tmax为 1.2 6h ,AUC(0→∞ ) 为 2 92 84 μg·ml-1,绝对生物利用度为 30 .0 3%。结论　穿琥宁肠溶胶囊有较好的生物利用度     

国产头孢克洛分散片药动学及生物利用度的研究

采用高效液相色谱法对９例健康志愿者交叉服用国产头孢克洛分散片及进口头孢克洛胶囊５００ｍｇ后，测定４ｈ内不同时间的血药浓度，以对国产和进口头孢克洛制剂进行药动学及生物利用度的研究。结果表明，国产分散片与进口胶囊的药－时曲线符合开放式一室模型，分散片的相对生物利用度为１０８．４％，分散片与胶囊的峰浓度分别为１３．４±３．３４７与１０．９９±２．８３５μｇ／ｍｌ；达峰时间分别为０．５５６８±０．１４５４与０．７３１５±０．１９１９ｈ；ＡＵＣ分别为１７．７０±２．８６０与１６．５２±３．７２６ｈμｇ／ｍｌ，上述各项药动学参数经配对ｔ检验表明ＡＵＣ与峰浓度均无统计学差异（Ｐ＞０．０５），但达峰时间有统计学差异（Ｐ＜０．０５）。同时经ＮＤＳＴ程序进行配对交叉设计的生物等效性检验，国产分散片与进口胶囊具有相同的生物药效性。     

Pharmacokinetics and bioavailability of the anti-emetic agent bromopride

The pharmacokinetics of bromopride, an anti-emetic agent chemically related to metoclopramide, has been investigated in normal human subjects. After intravenous bolus doses of 10 mg, a one-compartment open model appeared adequate to describe the plasma drug concentration data. The systemic clearance of bromopride was 899 ml min-1 +/- 22 per cent CV, the volume of distribution was 2151 +/- 16 per cent CV, and the elimination half-life was 2.9 h +/- 21 per cent CV. Over a wide drug concentration range of up to 650 ng ml-1, bromopride was only 40 per cent bound to plasma proteins. The systemic availability of orally and intramuscularly administered solution doses of 20 mg of bromopride was 54 per cent and 78 per cent, respectively. Formulation of bromopride as the solid material in capsules delayed absorption but did not affect the extent of drug bioavailability. The pharmacokinetics of bromopride appeared similar to that of metoclopramide. No evidence for non-linear kinetics was found when bromopride was administered orally in the dose range 10-30 mg: after single oral doses of 10, 20, and 30 mg, peak mean plasma drug concentrations were 20 ng ml-1 +/- 32 per cent CV, 38 ng ml-1 +/- 16 per cent CV, and 64 ng ml-1 +/- 23 per cent CV, respectively.     

醋酸甲羟孕酮胶丸的人体药动学研究及生物等效性评价

目的研究醋酸甲羟孕酮胶丸和醋酸甲羟孕酮胶囊在健康人体内的药物动力学和生物利用度,比较2种制剂的生物等效性。方法18名女性健康志愿受试者随机交叉单剂量口服500mg2种制剂,采用HPLC法测定血浆中药物浓度,计算出药动学参数,以醋酸甲羟孕酮胶囊为标准,通过方差分析和双向单侧t检验对胶丸剂的生物利用度和生物等效性进行比较。结果受试制剂和参比制剂的tmax分别为（2．28±0．46）、（2．28±0．46）h,Cmax为（336．16±33．40）、（334．67±36．36）ng·mL^-1,t1/2为（11．09±0．60）、（11．18±0．57）h,药时曲线下面积（AuC0-48）分别为（2359．22±257．75）、（2355．544±253．31）ng·h·mL^-1结论2种制剂生物等效,相对生物利用度为（100．69±10．93）％。     

The pharmacokinetics and absolute bioavailability of selegiline in the dog

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL^?1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL^?1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg^?1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 ± 9.56 min, 6.56 ± 0.56 L kg^?1, and 159.91 ± 19.28 mL min^?1 kg^?1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a t_max and C_max of 25 ± 5.8 min and 5.2 ± 1.36 ng mL^?1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 ± 3.31%.     

Pharmacokinetics and bioavailability of ergoloid mesylates

The pharmacokinetics and bioavailability of ergoloid mesylates following single administrations of various dose levels (3-9 mg), dosage forms (oral swallow and sublingual tablets, solution) and under different dosing conditions (fasted, with meal) were studied in young healthy volunteers. Male and female subjects showed a similar rate and extent of bioavailable ergoloid after drug treatment. The absorption of ergoloid using either the tablet dosage forms or the drug administered as a solution was rapid, with peak levels of about 60-80 pg ml-1 mg-1 dose achieved after 0.6 to 1.3 h. The elimination half-life for ergoloid in plasma was 2-5 h. Administration of drug with food had no effect on the extent of absorption (AUC) but lowered the absorption rate. This resulted in a reduction of (by 25 per cent) and delay in (by 1 h) achieving peak levels (Cmax). Increasing the ergoloid dose caused a proportional increase in the AUC, but a smaller than proportional increase for Cmax. The tablet formulations provided similar AUCs as the solution; the objective of the sublingual tablet formulation to provide improved bioavailability over the swallow tablet via circumvention of first-pass metabolism was therefore not realized. Transient decreases in blood pressure after ergoloid treatment paralleled the plasma level profiles. Higher ergoloid levels were paired with the larger pressure decreases.     

Pharmacokinetics and oral bioavailability of carbimide in man

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0.1, 0.3, 0.6, and 1 mg kg-1 and linear pharmacokinetics were observed for this dose range. Elimination half-life and total plasma clearance values ranged from 42 to 52 min and from 14.4 to 20.5 ml kg-1 min-1, respectively. After oral administration of 1 and 1.5 mg kg-1 of carbimide, elimination half-life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0.3 mg kg-1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10.5 to 15.5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0.3 and 1 mg kg-1 carbimide dose, respectively. The data indicate that there is a first-pass effect for carbimide.     

克拉霉素片剂与胶囊的药物动力学及相对生物利用度

8名健康志愿者交叉空腹口服克拉霉素胶囊和片剂各 5 0 0 mg后进行了药物动力学研究和相对生物利用度测定。结果表明 ,受试者单次空腹口服克拉霉素胶囊剂 5 0 0 mg后其体内过程符合血管外一室模型 ,其血药峰浓度 (Cmax)为 (2 .41± 0 .70 ) mg/ L,达峰时间 (Tmax)为 (1.81± 0 .88) h,药 -时曲线下面积 (AUC)为(2 1.83± 7.0 6 ) h· mg/ L ,2 4h累积尿排出率为给药量的 (36 .6 3± 9.33) % ,克拉霉素胶囊剂药代动力学参数与片剂相比差异均无统计学意义 (P>0 .0 5 )。以片剂 AUC为标准 ,克拉霉素胶囊剂的相对生物利用度为(94.0 4± 2 0 .2 7) %。受试者单剂空腹口服克拉霉素胶囊剂和片剂后的 AUC经双单侧检验法和 1～ 2 α置信区间法分析 ,结果表明克拉霉素胶囊剂与片剂具生物等效性     

健康受试者醋酸环丙孕酮片的生物等效性测定

目的:研究检测比较人体单次口服受试制剂醋酸环丙孕酮片和参比制剂醋酸环丙孕酮片的生物利用度。方法:18名男性健康志愿者采用两制剂双周期交叉试验设计,口服醋酸环丙孕酮片受试制剂和参比制剂各100mg,于不同时间采集血样,并采用高液相色谱法测定血药浓度。结果:受试者口服两种醋酸环丙孕酮片受试制剂和参比制剂后,T_(max)分别为(3.7±0.8)h和(3.9±0.5)h,C_(max)分别为(145.0±46.8)和(151.1±47.9)ng/ml,AUC0￣96分别为(2303.6±446.2)和(2182.2±426.5)ng/(h·ml)。醋酸环丙孕酮片受试制剂和参比制剂消除均较缓慢,消除半衰期分别为(29.4±10.3)和(26.4±7.4)h。AUC0￣96和C_(max)经对数转化后进行方差分析和双单侧t检验,T_(max)进行秩和检验,结果表明受试制剂的AUC0￣96、C_(max)和T_(max)与参比制剂比较差异无统计学意义。结论:醋酸环丙孕酮片受试制剂的人体相对生物利用度为(107.4±19.2)%,与参比制剂具有生物学等效性。     

Pharmacokinetics and bioavailability of oral ergometrine in male volunteers

The aim of this investigation was to assess the pharmacokinetics and bioavailability of ergometrine in six human male subjects after an oral dose of 0·200 mg and after an intravenous dose of 0·075 mg of ergometrine maleate. A large variation in bioavailability of between 34% and 117% in the six volunteers was observed. The lag time was also subject dependent and ranged between 0·0073 h (0.4 mm) and 0·47 h (28 min). After intravenous administration, the pharmacokinetic profile can be described by a twocompartment model. The distribution half-life t_1/2α is 0·18 ± 0·20 h, the elimination half-life t_1/2β is 2·0 ± 0·90 h, the total body clearance (CL) amounts to 35·9 ± 13·41 h^?1 and the steady-state volume (V_ss) of distribution is 73·4 ± 22·01. After oral administration, the pharmacokinetic profile can be described by a one-compartment model. The absorption half-life t_1/2abs is 0·19 ± 0·22 h, and the elimination half-life t_1/2β 1·90 ± 0·16 h. This study with oral ergometrine shows such a large interindividual variability in bioavailability that the oral route of administration does not seem not to be the most reliable means of accurate dosing in preventing post-partum haemorrhage.     

安宫黄体酮治疗药物流产后阴道出血32例临床分析

目的：探讨安宫黄体酮治疗药物流产后阴道出血的临床疗效。方法选取我院收治的64例药物流产后阴道出血患者,随机均分为对照组和观察组,对照组患者给予益母草颗粒口服,观察组患者给予安宫黄体酮片口服。比较两组患者的阴道出血持续时间、出血量和治疗总有效率的差异。结果观察组患者阴道出血持续时间和出血量均显著少于对照组（P＜0.05）;观察组治疗总有效率为90.6%,高于对照组的56.3%,两组比较差异有统计学意义（P＜0.05）。结论安宫黄体酮治疗药物流产效果确切,可显著缩短阴道出血持续时间和出血量。     

A stability-indicating HPLC method for medroxyprogesterone acetate in bulk drug and injection formulation

A stability-indicating HPLC assay method has been developed and validated for medroxyprogesterone acetate (MPA) in bulk drug and injectable suspension. An isocratic RP-HPLC was achieved on a Hichrom C₁₈ column (150 mm × 4.6 mm i.d., 5 μm) utilizing a mobile phase of methanol 0.020 M acetate buffer pH 5 (65:35, v/v) and a photodiode array detector at 245 nm. The stress testing of MPA was carried out under acidic and alkaline hydrolysis, and oxidation conditions. MPA was well resolved from its degradation products, a main related substance (megestrol acetate) and two preservatives (methyl paraben and propyl paraben) with the resolution ≥2. The proposed method was validated for selectivity, linearity, accuracy, precision and solution stability. The method was found to be suitable for the quality control of MPA in bulk drug and injections as well as the stability-indicating studies.     

盐酸伊托必利漂浮片在家犬体内的药物动力学

目的 研究自制盐酸伊托必利漂浮片在犬体内的药物动力学.方法 6只犬分别单剂景服用100 mg自制盐酸伊托必利漂浮片和市售盐酸伊托必利分散片,1周后两组交叉给药;采用HPLC法测定犬给药后不同时间的血药浓度.结果 盐酸伊托必利漂浮片、分散片的Tmax分别为6.62±1.05、1.94±0.31 h;Cmax分别为0.512±0.056、0.798 ±0.079 μg·ml-1;漂浮片的相对生物利用度是分散片的91.7%.结论 盐酸伊托必利漂浮片具有明显的缓释特征.     

Quantitative analysis and purity evaluation of medroxyprogesterone acetate by HPLC

A reversed-phase high-performance liquid chromatographic method was developed for the assay of medroxyprogesterone acetate and for the detection and determination of related steroids present as impurities in the drug. The method was compared with the normal-phase technique of the USP XX and was also applied to the analysis of tablets and injectable suspensions.     

Preparation of sterile long-acting injectable medroxyprogesterone acetate microcrystals based on anti-solvent precipitation and crystal habit control

ABSTRACT

Background: To overcome the rigorous aseptic process widely adopted by commercial long-acting injections, this work aimed to prepare a sterile MPA injection by manipulating the crystal habit through a bottom-up method.

Methods: The habit of the precipitated crystals was modified by changing the process conditions. Wherein, the cubic crystal (MPA-C) was obtained by mixing acetonitrile and water at a ratio of 1:4 (v/v) under an ultrasonic condition. Spherical crystal (MPA-S) was prepared with acetonitrile-water mixture (1:20, v/v). The addition of external additives could stop a certain crystal surface growth to obtain rod-like crystal (MPA-R) and branched crystal (MPA-B).

Results: All these crystals were proved to be of the same crystal form with different preferential growth orientation by PXRD, DSC, and SEM. The in vitro release of MPA-R microcrystal suspensions is faster than MPA-DP, while that of MPA-C is slightly slower. The relative bioavailability of MPA-C and MPA-R was 103.3% and 68.5%, respectively. The PK profile of MPA-C was most close to the commercial Depo-Provera® (MPA-DP) after intramuscular administration to male SD rats.

Conclusions: A cubic crystal of MPA was successfully prepared by anti-solvent precipitation method with the aid of sonication, providing an alternative strategy for the preparation of long-acting injections.     

非洛地平-美托洛尔透皮贴剂与缓释片在兔体内药动学及生物利用度比较

目的：研究非洛地平-美托洛尔复方透皮贴剂与两药市售缓释片在兔体内药动学和生物利用度差异。方法：采用三周期随机交叉试验法，6只健康白兔随机分为3组，分别给予复方非洛地平-美托洛尔静脉注射液、透皮贴剂及两药市售缓释片各l片，以气相色谱-电子捕获法分别测定非洛地平和美托洛尔血药浓度，用DAS软件计算药动学参数和生物利用度，通过统计学检验评价不同剂型间差异。结果：透皮贴剂较口服缓释片药物吸收时间显著延长（P〈0.05），达峰时间显著推后（P〈0．05），血药浓度平稳，波动性小，体内作用时间长达2d-3d。贴剂中非洛地平和美托洛尔的生物利用度分别是其口服缓释片的114．30％和192．92％。结论：该贴荆缓释特征明显，达到了预期提高生物利用度、延长药物体内驻留时间、维持平稳血药浓度和方便用药的新剂型设计目的。     

Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment

Objective To evaluate the effect of moderate liver impairment on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093, ESL), a novel voltage-gated sodium channel blocker currently in clinical development. Methods The pharmacokinetics of ESL following an administration regimen of 800 mg once-daily for 8 days was characterized in patients with moderate liver impairment (n = 8) and in subjects with normal liver function (n = 8, control group). Results Eslicarbazepine acetate was rapidly and extensively metabolized by first-pass metabolism to its main active metabolite, eslicarbazepine (S-licarbazepine). There were more subjects with measurable plasma concentrations of the parent drug (ESL) in the hepatic impairment group than in the control group, suggesting that first-pass metabolism was slightly decreased by liver impairment. However, ESL plasma concentrations remained very low, representing only about 0.01% of total systemic exposure. No differences in the pharmacokinetics of eslicarbazepine or its metabolites were found between the hepatic impairment and control groups. Urinary excretion of eslicarbazepine and its glucuronide form was similar in the liver impaired and control subjects. The sum of drug moieties recovered in the urine corresponded to 91% of the administered dose in the control group and to 84% of the administered dose in the liver impairment group. Conclusion The pharmacokinetics of ESL was not affected by moderate hepatic impairment. Therefore, patients with mild to moderate liver impairment treated with ESL do not require dosage adjustment.     

Pharmacokinetics and bioavailability of etintidine in beagle dogs: Effects of routes of administration,doses, dosage forms,and chronic dosing

Etintidine HCl is an H₂ receptor antagonist which has been under clinical trial for the treatment of duodenal ulcer diseases. Our studies are to determine the effects of routes of administration, doses, dosage forms, and chronic dosing on the bioavailability and pharmacokinetics of etintidine (E) in the beagle dog. Salient findings are:

• 1 Plasma levels of etintidine after i.v. administration of 200mg of E followed a 3-exponential decay with a terminal t_½ of 1.7 h.
• 2 Following oral administration of 200mg of E in capsules, tablets, or a solution dosage form to dogs, etintidine was rapidly and nearly completely absorbed with no significant first-pass elimination.
• 3 A proportional increase in the amount of etintidine absorbed in the dogs occurred as the administered doses increased from 30 to 180 mg kg^?1 and this relationship did not change with repeated dosing.
• 4 Some accumulation of etintidine took place during the 52 weeks of chronic dosing.

     

中国妇女单次及多次注射cyclofem后血中醋酸甲羟孕酮的药代动力学

目的比较中国妇女单次及连续肌注cyclofem后血中醋酸甲羟孕酮(MPA)的药代动力学变化 ,为长期应用该长效避孕针的安全性提供依据。方法9名健康育龄妇女每月一次肌注cyclofem微晶水混悬剂(醋酸甲羟孕酮25mg 环戊丙酸雌二醇5mg) ,持续一年。于用药第1、6和12个月的临注射前和注射后不同时间取血 ,采用自身对照比较此三个给药周期MPA的药代动力学特征。结果首次及第6、12次注射后 ,血中MPA分别于3.4±0.9、4.3±2 2及3 7±2.6天达峰浓度 ;MPA平均峰值血药水平(Cmax)为3.75±1.27、5.54±1.79及5.55±1.80nmol/L ;AUC0 -28 分别为55.84±28.15、95.45±26.56及98.81±21.84nmol/(L·d)。MPA的药代动力学存在明显的个体差异。三个给药周期MPA体内平均滞留时间(MRT)无显著变化 ,分别为11.98±1.08、12.77±0.47和12.43±0.64天。与首次注射后相比 ,第6个给药周期MPA的Cmax 和AUC0 -28显示有增高的倾向 ,但在其后6个月中 ,上述参数未见明显差别。结论连续使用每月一次避孕针cyclofem并不引起受试者体内MPA的明显蓄积     

Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes

Objective Medroxyprogesterone acetate (MPA), frequently used in contraception and chemotherapy, was involved in a report of drug-drug interaction (DDI) when co-administrated with phenytoin, doxifluridine and cyclophosphamide. In order to clarify the mechanism of such interaction, an in vitro study was undertaken to evaluate MPA’s potential to inhibit cytochrome P450 (CYP) enzymes.Methods Inhibitory effects of MPA on seven CYPs, including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, were conducted in human liver microsomes. Time- and NADPH-dependent inhibitions were also tested. DDI potential was predicted according to the [I]/K _i value.Results MPA was found to inhibit CYP2C9 and CYP3A4; half inhibition concentration (IC₅₀) was 16.1 μM and 31.5 μM, respectively. Slight inhibition was observed on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 with IC₅₀ of more than 100 μM. MPA exhibited activation rather than inhibition on CYP2E1. Further study revealed that MPA showed a noncompetitive inhibition on CYP2C9 and a competitive inhibition on CYP3A4 with K _i of 9.0 μM and 36 μM, respectively. In addition, MPA was not a mechanism-based inhibitor to any of seven isoforms tested. By using predicted concentration of MPA in liver, [I]/K _i was estimated to be 0.24 and 0.06 for CYP2C9 and CYP3A4, respectively. The concentration of phenytoin co-administrated with MPA was calculated to increase by 24%.Conclusion Based on our results, MPA can possibly cause clinically relevant DDI via the inhibition of CYP2C9.