Pharmacokinetic studies of meloxicam following oral and transdermal administration in Beagle dogs

Aim： The potential for topical delivery of meloxicam was investigated by examining its pharmacokinetic profiles in plasma and synovial fluid following oral and transdermal administration in Beagle dogs.
Methods： The experiment was a two-period, crossover design using 6 Beagle dogs. Meloxicam tablets were administered orally at a dose of 0.31 mg/kg, and meloxicam gel was administered transdermally at a dose of 1.25 mg/kg. Drug concentrations in plasma and synovial fluid were determined by liquid chromatography-tandem mass spectrometry （LC/MS/MS）. The pharmacokinetic parameters were calculated using the Topfit 2.0 program. Results： The pharmacokinetic results showed that AUC0-t （23.9±8.26 pg·h·mL^-1） in plasma after oral administration was significantly higher than after transdermal delivery （1.00±0.43 pg·h·mL^-1）. In contrast, the ratio of the average concentration in synovial fluid to that in plasma following transdermal administration was higher than that for an oral delivery. The synovial fluid concentration in the treated leg was much higher than that in the untreated leg, whereas the synovial fluid concentration in the untreated leg was similar to the plasma concentration.
Conclusion： The high concentration ratio of synovial fluid to plasma indicates direct penetration of meloxicam following topical administration to the target tissue. This finding is further supported by the differences observed in meloxicam concentrations in synovial fluid in the treated and untreated joints at the same time point. Our results suggest that transdermal delivery of meloxicam is a promising method for decreasing its adverse systemic effects.     

Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing

The pharmacokinetics of a new serotonin 5-HT₂ antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg⁻¹ and intravenous doses of 1, 3 and 6 mg kg⁻¹ were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg⁻¹ doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45–61%. Deramciclane had a large volume of distribution (32–37 L kg⁻¹) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h⁻¹) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC_0–∞ increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N-desmethyl deramciclane, was also nonlinear (p =0.0002). At steady state deramciclane accumulated less than 2-fold during repeated administration. Copyright © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic modeling and simulation for dose rationale of doripenem in neonates and infants

The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients <3 months of age using Monte-Carlo pharmacokinetic/pharmacodynamic (PKPD) simulations. In the population pharmacokinetic analysis using 187 plasma concentrations from 47 neonates and infants, a two-compartment model well described plasma doripenem concentrations with the most significant covariates of chronological age and gestational age identified for the pharmacokinetics of doripenem. Monte-Carlo simulations suggested that the selected dosages for neonates and infants based on chronological age and gestational age (5 or 10 mg/kg) would provide ≥90% target attainment of 40%fT_>MIC against MIC of 2 μg/mL in all age groups. These results would be useful for understanding the PKPD characteristics of doripenem, which could provide essential information on optimal therapeutic treatment for neonates and infants.     

利用蒙特卡洛模拟对不同体质量患者使用头孢菌素类药物预防外科手术部位感染的给药方案优化

目的: 应用蒙特卡洛模拟评价和优化不同体质量患者预防外科手术部位感染的头孢菌素类药物给药方案。方法: 使用临床常见的给药剂量, 以% fT＞4MIC为药动学/药效学(PK/PD) 目标, 选择群体药动学数据为PK参数, 通过比较目标菌种的累积反应分数(cumulative fraction of response, CFR), 评价疗效和优化出最佳给药方案。结果: 正常体质量患者使用头孢唑啉预防金黄色葡萄球菌, 在3 h内所有CFR＞90%;预防大肠埃希菌, 使用2 g在2 h内, 或3 g在3 h内有效。超正常体质量患者预防金黄色葡萄球菌, 使用2 g在2 h内CFR＞90%;预防大肠埃希菌, 使用3 g在2 h内CFR＞90%。1.5 g头孢呋辛在1 h内CFR＞90%。正常体质量患者使用3 g预防金黄色葡萄球菌, 大肠埃希菌和凝固酶阴性葡萄球菌时, 大部分能在2 h内达到有效预防效果。超正常体质量患者剂量为3 g, 预防金黄色葡萄球菌和凝固酶阴性葡萄球菌结果提示2 h内预防有效; 预防大肠埃希菌, 仅部分结果显示在1 h内CFR＞90%。结论: 头孢唑啉对不同体质量的患者给药方案不同, 正常体质量患者选择"2 g, q2 h"或"2 g, q3 h"的给药方案, 超正常体质量患者选择"3 g, q2 h"的给药方案。头孢呋辛对正常和超正常体质量患者均选择"3 g, q2 h"的方案。     

单剂量加替沙星口服在Beagle犬体内药代动力学研究

目的:探讨加替沙星口服后在Beagle犬体内药代动力学特征。方法:选取12只Beagle犬分为三个剂量组,分别单剂给予加替沙星34 mg/kg1、7 mg/kg、8.5 mg/kg口服后0.5、1.0、2.0、4.0、6.0、8.0、12.0、24.0、36.0、48.0、60.0 h取血,高效液相色谱法测定血中药物浓度,3p97程序计算药动学参数。结果:大、中、小剂量组动物T1/2ka分别为(2.64±1.00)h、(1.43±0.90)h和(2.00±0.53)h;T1/2ke分别为(7.33±1.79)h(、6.32±3.28)h和(5.34±2.60)h;Tmax分别为(6.32±2.32)h(、5.77±1.62)h和(3.95±2.18)h;Cmax分别为(6.31±2.66)μg/mL(、2.67±0.64)μg/mL和(0.64±0.30)μg/mL;AUC0→60分别为(110.86±43.76)μg/(mL.h)、(41.93±5.58)μg/(mL.h)和(8.58±2.70)μg/(mL.h)。结论:加替沙星口服易吸收,血药浓度高,代谢较慢,有益于临床应用。     

Bioavailability studies with etodolac in dogs and man

The effects of formulation, particle size, coadministration of food, antacids, or antiulcer agents on the bioavailability of etodolac (ULTRADOL, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid), a novel non-steroidal anti-inflammatory agent, have been evaluated in dogs and man. The effects of dosage regimen and/or repetitive dosing on bioavailability were also determined. In man, capsule and tablet dosage forms containing micronized etodolac were shown to have a bioavailability (AUC) equal to that of the reference etodolac solution. Etodolac from tablets and capsules was rapidly absorbed since only minor decreases in Cmax and increases in tmax were observed compared to the etodolac solution. In a comparison of regular and micronized etodolac dosage forms, both in dogs and man, similar findings, i.e. no change in AUC but small parallel changes in Cmax and tmax, were noted. Administration of etodolac with food had no effect on etodolac bioavailability in dogs but tended to cause a delay in its absorption. Coadministration of an antacid, magaldrate, or the antiulcer agent, sucralfate, had no effect on the bioavailability of etodolac in dogs, although with the latter, a significant reduction in Cmax was noted. In man, etodolac may be administered as a single bolus dose or in divided (b.i.d.) doses without any loss in bioavailability. With either regimen, on repeat administration for 7 days, no etodolac accumulation was noted.     

氯吡格雷单次和多次给药在大鼠体内的药动学特征

目的建立并确证氯吡格雷羧酸代谢物SR26334血浆药物浓度的HPLC检测法,研究氯吡格雷单次和多次大剂量给药后在大鼠体内的药动学特征。方法12只SD大鼠随机分成2组（单次给药组和多次给药组）,单次和多次灌胃给予氯吡格雷30mg·kg-1,多次给药为每天1次,共7d。采用HPLC法测定给药后不同时间点血浆中SR26334浓度,用DAS3．0处理经时血药浓度数据,计算主要药动学参数。结果单次给药和多次给药后SR26334血药浓度均于给药后约1h达峰,pmax分别为（35．57±10．25）mg·L。和（54．28±10．39）mg·L-1;两者g1／2z相近,分别为（6．88±1．54）h和（6．54±1．04）h;AUC0—24h分别为（304．63±63．07）mg·h·L-1和（543．81±43,27）mg·h·L-1;AUC0-∞分别为（334．00±66．24）mg·h·L-1和（594．91±46．84）mg·h·L-1;Vz／F分别为（0．92±0．23）L·kg。和（0．48±0．07）L·kg-1;CLz／F分别为（0．09±0．02）L·h-1·kg-1和（0．05±0．00）L·h-1·kg-1。结论氯吡格雷单次与多次给药后的主要药动学参数AUC0-24h、AUC0-∞、Vz／F、ck／F和pmax差异具有统计学意义（P〈0．01,P〈0．05）,说明多次大剂量给药时其代谢物SR26334在体内有蓄积。     

美他沙酮在Beagle犬体内的药物动力学

目的建立专属、灵敏、高效的LC/MS/MS法,研究美他沙酮在Beagle犬体内的药物动力学。方法以Zorbax SB-C18为色谱柱,水(含体积分数为0.2%的甲酸)-乙腈(体积比为50:50)为流动相;选用ESI离子源,多反应监测方式进行检测。犬以80 mg.kg-1口服美他沙酮后,采集血浆样品。采用已建立的LC/MS/MS法测定美他沙酮血浆浓度,计算药物动力学参数。结果美他沙酮线性为0.05～10.00 mg.L-1(r=0.997 2)。日内和日间精密度均小于12.2%,准确度均在8.19%之内。美他沙酮口服给药后在Beagle犬体内的主要药物动力学参数如下:t1/2为(4.02±3.04)h,tmax为(1.5±0.35)h,ρmax为(1 402.31±653.96)mg.L-1,AUC(0→24)为(2 735.72±1 264.67)mg.L-1,AUC(0→∞)为(3 109.72±1 283.57)mg.L-1。结论本方法适用于美他沙酮的药物动力学研究。     

哌拉西林他唑巴坦在肾内科患者中的群体药动学和蒙特卡罗模拟

目的:建立哌拉西林他唑巴坦在肾内科患者中的群体药动学模型,应用蒙特卡罗模拟优化其给药方案,以促进个体化给药.方法:采用高效液相色谱法测定50名肾内科患者静脉滴注哌拉西林-他唑巴坦的血清浓度310例次并收集相关临床指标,运用非线性混合效应模型(NONMEM)程序建立群体药动学模型.采用蒙特卡罗模拟(Monte Carlo simulation, MCS)比较哌拉西林他唑巴坦的不同给药方案对不同MIC群体的药效学目标到达.结果:哌拉西林、他唑巴坦的药动学符合一室模型,群体典型值及个体间差异(Between Subject Variability,BSV)分别为:哌拉西林CL/F=13.74 L·h^-1,BSV=11.1%;V/F=21.69 L,BSV=8.0%,他唑巴坦CL/F=9.32 L·h^-1, BSV=9.11%;V/F=16.0 L, BSV=5.28%;固定效应参数中,肌酐清除率对参数有影响.对于MIC值较大的细菌,延长输注的给药方案获得了更高的目标的累积反应分数(CFR).结论:群体药动学模型和蒙特卡罗模拟,可为调整哌拉西林他唑巴坦的治疗方案提供有效的分析手段.     

Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects

Summary The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infusion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study. Both treatments were generally well tolerated and no relevant compound-related adverse events were noted. The plasma pharmacokinetics of pantoprazole following intravenous infusion in this group of subjects were characterised by a total plasma clearance of 0.13 l·h⁻¹·kg⁻¹ and apparent terminal elimination half-life 1.9 h. The apparent volume of distribution estimated at steady state (0.171·kg⁻¹) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid attainment of maximum plasma concentrations of pantoprazole. Pantoprazole was well absorbed following oral administration; the absolute systemic bioavailability of the compound was estimated as 77% (95% CI, 67 to 89%).     

四氢小檗红碱及其前药的比格犬药代动力学研究

目的建立同时定量检测比格犬全血中抗焦虑新药四氢小檗红碱(THB)及其前药9-乙酰四氢小檗红碱硫酸盐(ATHBS)的LC-MS/MS方法,并研究四氢小檗红碱在比格犬体内的药代动力学及生物利用度。方法建立检测全血中THB和ATHBS的LC-MS/MS方法,进行专属性、线性、回收率、稳定性、精密度和准确度等方法学验证。比格犬单次口服和静脉注射3 mg.kg-1ATHBS后考察了前药与活性代谢产物THB的血药浓度-时间变化,应用WinNonlin软件得到药代动力学参数和口服生物利用度。结果 ATHBS和THB在2～2 000μg·L-1的浓度范围内呈良好的线性(r>0.9985),定量下限均为2μg·L-1。THB和ATHBS的回收率分别大于78.74%和75.52%,日内和日间精密度(RSD)均在10.79%之内,准确度(RE)在-10.3%～3.92%的范围内。比格犬单次静注和口服ATHBS后,前药均能快速转化成为活性产物,血中浓度在60 min降至检测限之下。静注组THB在2 min达峰,Cmax为(605.99±102.88)μg·L-1,消除半衰期T12为(7.03±1.77)h,AUC(0-t)为(718.64±143.01)h·μg·L-1。口服组THB在15min达到(77.71±26.60)μg.L-1的峰值,药-时曲线在6 h出现第2个小峰,T 12为(5.89±3.95)h,AUC(0-t)为(179.62±91.64)h·μg·L-1,口服生物利用度为26.2%。结论建立的LC-MS/MS定量方法快速、简便、灵敏,可用于同时研究前药和THB的药代动力学。比格犬口服或静注ATHBS后,前药在体内可快速转化成为活性产物,THB达峰迅速,血药浓度消除较快,口服生物利用度较好。     

Interspecies differences on pharmacokinetics of rebamipide following oral administration to rats and dogs

Rebamipide is used widely in East Asia for the treatment of gastric ulcers, acute gastritis, and exacerbated chronic gastritis. The objective of this study was to investigate the pharmacokinetic (PK) properties of rebamipide following single oral administration in rats and dogs. Eleven rats and dogs received single oral administrations of rebamipide (35 mg/kg and 100 mg, respectively). Blood samples were collected according to the assigned schedule, and the plasma concentration of rebamipide was determined using liquid chromatography–tandem mass spectrometry. A double-peak phenomenon was observed in the PK profile of rebamipide in rats. In contrast, rebamipide showed a conventional PK profile without double peaks in dogs. The half-life of rebamipide in rats (12.85 ± 7.86 h) was longer than that in dogs (5.62 ± 2.24 h), and the apparent total clearance (Cl_t/F) of rebamipide in rats (3.32 ± 1.18 L/h) was lower than that in dogs (105.01 ± 42.37 L/h). Simple allometric approaches showed that the correlation between body weight and Cl_t/F (R² = 0.9287) among rats, dogs, and humans appeared satisfactory. This finding will help not only in understanding the pharmacology of rebamipide but also in establishing a strategy for in vivo evaluation of novel rebamipide formulations.     

Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration

Dextromethorphan is an N‐methyl‐D‐aspartate (NMDA) non‐competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg. Blood samples were collected at time 0 and at various times up to 96 h post drug administration. Urine samples were collected from 12 horses up to 120 h post administration. Plasma and urine samples were analyzed using liquid chromatography‐mass spectrometry, and the resulting data analyzed using non‐compartmental analysis. The C_max, T_max, and the t_1/2 of dextromethorphan were 519.4 ng/mL, 0.55 h, and 12.4 h respectively. The area under the curve of dextromethorphan, free dextrorphan, and conjugated dextrorphan were 563.8, 2.19, and 6,691 h*ng/mL respectively. In addition to free and glucuronidated dextrorphan, several additional glucuronide metabolites were identified in plasma, including hydroxyl‐desmethyl dextrorphan, desmethyl dextrorphan, and three forms of hydroxylated dextrorphan. Dextromethorphan was found to be eliminated from the urine predominately as the O‐demethylated metabolite, dextrorphan. Several additional metabolites including several novel hydroxy‐dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms. No significant undesirable behavioural effects were noted throughout the duration of the study. Copyright © 2016 John Wiley & Sons, Ltd.     

Pharmacokinetic and pharmacodynamic studies following the intravenous and oral administration of the antiparkinsonian drug biperiden to normal subjects

Summary The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects.After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml·min^–1·kg^–1 and 24 l·kg^–1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism.Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.     

四季青中原儿茶酸在beagle犬体内的药动学研究

目的 建立LC-MS/MS法测定血浆中原儿茶酸的浓度,并对beagle犬灌胃四季青水煎液后原儿茶酸的药动学进行研究。方法 Beagle犬血浆样品以酮洛芬为内标,用乙腈沉淀蛋白,采用LC-MS/MS法进行分离和测定。色谱柱为C18(4.6mm×100mm, 2.7μm);流动相为80%乙腈-20%水(含0.1%甲酸),流速为0.2mL/min,柱温为30℃。质谱条件：电喷雾离子源(ESI),负离子模式,多反应离子监测(MRM),检测离子为原儿茶酸m/z 153.0→109.0,内标酮洛芬m/z 253.1→209.1。6只beagle犬单次灌胃四季青水煎液50mL(0.2g/mL)后,于给药前及给药后0.083、0.167、0.333、0.5、0.667、0.833、1、1.5、2、3、4和6h采血,以LC-MS/MS法测定原儿茶酸在beagle犬体内的血浆浓度,并用非房室模型计算药动学参数。结果 原儿茶酸浓度在0.05~2.00μg/mL范围内线性关系良好,定量下限为0.05μg/mL,批内和批间精密度RSD均小于8.6%,准确度为92.3%~102.0%。Beagle犬分别单次灌胃1g/kg(生药量)四季青水煎液后,其主要药动学参数Cmax为(1.53±0.33)μg/mL,Tmax为(0.42±0.09)h,t1/2为(0.80±0.16)h,MRT0~t 为(1.04±0.14)h,MRT0~∞ 为(1.32±0.26)h,AUC0~t为(1.90±0.35)(μg/mL)·h,AUC0-∞为(2.02±0.33)(μg/mL)·h。 结论 本实验中建立的LC-MS/MS法专属性强、快速灵敏,可以用于犬血浆中原儿茶酸的测定。Beagle犬单次灌胃四季青水煎液后,血浆中原儿茶酸能快速吸收,达峰速度较快,在体内能滞留一定时间,有利于四季青药效作用的发挥。     

Pharmacokinetic and pharmacodynamic studies following oral administration of erythropoietin mucoadhesive tablets to beagle dogs

Oral administration of mucoadhesive tablets containing erythropoietin (EPO) and an absorption enhancer Labrasol was studied in rats and dogs. Mucoadhesive tablets were prepared using Sylysia 550 holding the absorption enhancer and Carbopol 974P as a mucoadhesive agent. Mucoadhesive tablets were covered with a water-insoluble backing layer made of cellulose acetate and a pH-sensitive covering layer made of Eudragit L/Eudragit S. Tablet was administered into the rat jejunum at EPO dose of 100 IU/kg and serum samples were collected for 6 h. Serum EPO level was analysed with a standard ELISA procedure. After administration, rats showed a maximum serum EPO level of C_max 70.6 ± 8.9 mIU/ml. Oral administration of a single tablet containing 100 IU/kg EPO to beagle dogs showed a C_max of 24.6 ± 4.1. When EPO dose was increased to 500 IU/kg and the number of tablets was also increased to 5, the C_max was 54.8 ± 9.0 mIU/ml. However, when EPO, 100 IU/kg dose was divided into five tablets, the C_max was 15.5 ± 1.8 mIU/ml. In the absence of absorption enhancer, the C_max was 35.8 ± 3.8 with 500 IU/kg dose distributed among five tablets. Pharmacodynamic studies were carried out following oral administration of mucoadhesive tablets for 6 consecutive days at an EPO dose of 500 IU/kg. Whole blood samples were collected and percent circulating reticulocytes were counted using Miller technique. The increase in percent circulating reticulocytes was found to be 1.7% on day 8 following oral administration. As a control study, EPO was administered by i.v. route at a dose of 300 IU/kg for 3 consecutive days and the percent circulating reticulocytes were counted. Mucoadhesive tablets showed promising results as an oral drug delivery system for protein therapeutics.     

Pharmacokinetic evaluation in dogs of theophylline in a novel zero-order release core-in-cup tablet

A new core-in-cup tablet that is manufactured from a novel adjustable punch, has been formulated and evaluated for its ability to release with subsequent absorption of theophylline via a zero-order rate of absorption. The core-in-cup tablets were compared with core only tablets and immediate release capsules. Pharmacokinetic parameters used to test the effectiveness of the formulations included, elimination rate, rate and kinetic order of absorption, relative availability as compared with an immediate release capsule of pure theophylline, and percentage area under the curve fluctuation (%AUCF) at steady state. The correlation coefficient, Akaike's information criterion (AIC) and the F -ratio probability were used to test the applicability of a zero-order, first-order, or square root of time model, for the rate of release of theophylline from the core-in-cup and core only tablets. The zero-order rate model was most applicable to the core-in-cup tablet, whereas the square root of time release model was most applicable to the core only tablet. The average %AUCF for the core-in-cup tablet was 9.26±3.15 while that for the core only tablet was 16.19±2.37 (p =0.0545). The results of this study suggest that the core-in-cup tablet is a versatile zero-order release rate dosage form that are simple to produce. © 1998 John Wiley & Sons, Ltd.     

大鼠一次性灌服酸枣仁提取物后棘苷的药代动力学研究

目的用反相高效液相色谱法,以磺胺甲唑为内标,对一次性ig酸枣仁提取物后的大鼠血浆中棘苷进行药代动力学研究。方法血浆样品经乙腈沉淀蛋白后,于50 ℃氮气流下吹干,残渣用流动相溶解后进行分析。色谱条件为色谱柱:Hypersil C₁₈柱,200 mm×4.6 mm ID,5 μm;流动相:乙腈-水-冰醋酸(15∶85∶1);流速:0.7 mL·min^-1;检测波长:334 nm;柱温:35 ℃。结果血浆中棘苷在18.1～903.5 μg·L^-1成良好线性关系(R²≥0.995)。平均回收率为94.5%,日内、日间精密度RSD均小于9.0%。该法定量限为18.1 μg·L^-1,血浆样品在-20 ℃可稳定保存。结论该法简便、灵敏、准确,可用于大鼠一次性灌服酸枣仁提取物后血浆中棘苷的浓度测定及其药代动力学研究。