Pharmacokinetics of articaine hydrochloride and its metabolite articainic acid after subcutaneous administration in red deer (Cervus elaphus)

AIM: To develop and validate a simple and sensitive method using liquid chromatography-mass spectrometry (LC-MS) for quantification of articaine, and its major metabolite articainic acid, in plasma of red deer (Cervus elaphus), and to investigate the pharmacokinetics of articaine hydrochloride and articainic acid in red deer following S/C administration of articaine hydrochloride as a complete ring block around the antler pedicle.

METHODS: The LC-MS method was validated by determining linearity, sensitivity, recovery, carry-over and repeatability. Articaine hydrochloride (40?mg/mL) was administered S/C to six healthy male red deer, at a dose of 1?mL/cm of pedicle circumference, as a complete ring block around the base of each antler. Blood samples were collected at various times over the following 12 hours. Concentrations in plasma of articaine and articainic acid were quantified using the validated LC-MS method. Pharmacokinetic parameters of articaine and articainic acid were estimated using non-compartmental analysis.

RESULTS: Calibration curves were linear for both articaine and articainic acid. The limits of quantifications for articaine and articainic acid were 5 and 10?ng/mL, respectively. Extraction recoveries were >72% for articaine and >68% for articainic acid. After S/C administration as a ring block around the base of each antler, mean maximum concentrations in plasma (C_max) of articaine were 1,013.9 (SD 510.1) ng/mL, detected at 0.17 (SD 0.00) hours, and the C_max for articainic acid was 762.6 (SD 95.4) ng/mL at 0.50 (SD 0.00) hours. The elimination half-lives of articaine hydrochloride and articainic acid were 1.12 (SD 0.17) and 0.90 (SD 0.07) hours, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE: The LC-MS method used for the quantification of articaine and its metabolite articainic acid in the plasma of red deer was simple, accurate and sensitive. Articaine hydrochloride was rapidly absorbed, hydrolysed to its inactive metabolite articainic acid, and eliminated following S/C administration as a ring block in red deer. These favourable pharmacokinetic properties suggest that articaine hydrochloride should be tested for efficacy as a local anaesthetic in red deer for removal of velvet antlers. Further studies to evaluate the safety and residues of articaine hydrochloride and articainic acid are required before articaine can be recommended for use as a local anaesthetic for this purpose.     

Pharmacokinetic profiles of the two major active metabolites of metamizole (dipyrone) in cats following three different routes of administration

This study was performed to determine pharmacokinetic profiles of the two active metabolites of the analgesic drug metamizole (dipyrone , MET), 4‐methylaminoantipyrine (MAA), and 4‐aminoantipyrine (AA), after intravenous (i.v., intramuscular (i.m.), and oral (p.o.) administration in cats. Six healthy mixed‐breed cats were administered MET (25 mg/kg) by i.v., i.m., or p.o. routes in a crossover design. Adverse clinical signs, namely salivation and vomiting, were detected in all groups (i.v. 67%, i.m. 34%, and p.o. 15%). The mean maximal plasma concentration of MAA for i.v., i.m., and p.o. administrations was 148.63 ± 106.64, 18.74 ± 4.97, and 20.59 ± 15.29 μg/ml, respectively, with about 7 hr of half‐life in all routes. Among the administration routes, the area under the plasma concentration curve (AUC) value was the lowest after i.m. administration and the AUC_EV/i.v. ratio was higher in p.o. than the i.m. administration without statistical significance. The plasma concentration of AA was detectable up to 24 hr, and the mean plasma concentrations were smaller than MAA. The present results suggest that MET is converted into the active metabolites in cats as in humans. Further pharmacodynamics and safety studies should be performed before any clinical use.     

亚硒酸钠在低硒籽鹅体内药物代谢动力学的研究

研究亚硒酸钠在低硒籽鹅体内的药物代谢动力学,为临床合理地用药预防籽鹅缺硒病提供科学依据。选择1日龄健康籽鹅80只（公母各半）作试验动物,复制缺硒动物模型后,口服0.1%亚硒酸钠溶液,分别于投药后第0、1、2、4、8、12、24、48、72、96、144、192 h剖杀籽鹅,采取心脏、肝脏、肾脏、脾脏、胰脏、肌胃、肌肉组织样品,应用2,3—二氨基萘荧光法测定各组织中的硒含量,应用MCPKP软件计算药动学参数。肝脏、肾脏、脾脏、胰脏、肌胃均符合一级吸收二室开放模型,肌肉符合滞后一级吸收一室开放模型,心脏符合一级吸收一室开放模型。硒在肝脏中吸收最快,其次为心脏、肌胃、胰脏、肾脏、脾脏,肌肉吸收最慢;硒的消除都比较慢,最快的为肌肉,其次为心脏、肝脏、脾脏、肾脏、胰脏、肌胃。亚硒酸钠在低硒籽鹅不同组织中吸收、分布和消耗时间不同,这主要是由于硒缺乏损伤了动物机体的某些组织器官所致。     

2种头孢氨苄片在比格犬体内的药代动力学及生物等效性试验

【目的】研究头孢氨苄片受试制剂和参比制剂在比格犬体内的生物等效性。【方法】采用双周期和双序列交叉设计,将22只健康比格犬随机分成2组,按30 mg/kg BW分别单剂量口服头孢氨苄片受试制剂Trolevis~?300和参比制剂Rilexine~?300,于给药前(0 h)和给药后0.5、1、1.5、2、2.5、3、4、6、8、12、17和24 h从臂头静脉采血。对超高效液相色谱串联质谱(UPLC-MS/MS)方法进行特异性、线性、检测限、准确度、精密度、稳定性等方法学考察。利用建立好的UPLC-MS/MS方法测定血浆中的药物浓度,并用WinNonlin^TM 8.1软件对药代动力学参数进行分析计算。【结果】方法学结果显示,在100～5 000 ng/mL浓度范围内相关性良好,相关系数(R²)≥0.99,标准曲线方程为y=10.6828x-176.481;高、中、低3个浓度的相对回收率平均值分别为105.63%、104.35%和102.40%;日内和日间变异系数均<15%;检测限为50 ng/mL,定量限为100 ng/mL。药代动力学结果...     

Pharmacokinetics of xylazine after 2-, 4-, and 6-hr durations of continuous rate infusions in horses

Intravenous (i.v.) bolus administration of xylazine (XYL) (0.5 mg/kg) immediately followed by a continuous rate infusion (CRI) of 1 mg kg⁻¹ hr⁻¹ for 2, 4, and 6 hr produced immediate sedation, which lasted throughout the duration of the CRI. Heart rate decreased and blood pressure increased significantly (p > .05) in all horses during the first 15 min of infusion, both returned to and then remained at baseline during the duration of the infusion. Compartmental models were used to investigate the pharmacokinetics of XYL administration. Plasma concentration–time curves following bolus and CRI were best described by a one-compartment model. No differences were found between pharmacokinetic estimates of the CRIs for the fractional elimination rate constant (K_e), half-life (t_1/2e), volume of distribution (V_d), and clearance (Cl). Median and range were 0.42 (0.15–0.97)/hr, 1.68 (0.87–4.52) hr, 5.85 (2.10–19.34) L/kg, and 28.7 (19.6–39.5) ml min⁻¹ kg⁻¹, respectively. Significant differences were seen for area under the curve ( ) (p < .0002) and maximum concentration (C_max) (p < .04). This indicates that with increasing duration of infusion, XYL may not accumulate in a clinically relevant way and hence no adjustments are required in a longer XYL CRI to maintain a constant level of sedation and a rapid recovery.     

Fractionated oral dosing and its effect on cyclophosphamide pharmacokinetics in dogs with high-grade multicentric lymphoma

Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200–250 mg/m² over 3 to 4 days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h⁻¹; p = .125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h × ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200–250 mg/m².     

Pharmacokinetics and Metabolism Study of Deep-Sea-Derived Butyrolactone I in Rats by UHPLC–MS/MS and UHPLC–Q-TOF-MS

Butyrolactone I (BTL-I) is a butanolide isolated from the deep-sea-derived fungus, Aspergillus sp. It provides a potential new target for the prevention and treatment of food allergies. This study aimed to investigate the metabolic and pharmacokinetic profile of BTL-I in rats. The metabolic profiles were obtained by UHPLC–Q-TOF-MS. As a result, eleven metabolites were structurally identified, and the proposed metabolic pathways of BTL-I were characterized. The main metabolites were the oxidative and glucuronidative metabolites. In addition, a sensitive UHPLC–MS/MS method was established for the quantitation of BTL-I in rat plasma (LOQ = 2 ng/mL). The method was fully validated and successfully applied to the pharmacokinetic study of BTL-I in rats after oral administration or intravenous administration. The oral bioavailability was calculated as 6.29%, and the maximum plasma concentrations were 9.85 ± 1.54 ng/mL and 17.97 ± 1.36 ng/mL for intravenous and intragastric dosing groups, respectively.     

磺胺-6-甲氧嘧啶在肉鸡体内的药代动力学

本研究以B—M比色法和高效液相色谱(HPLC)法为定量手段,探讨了磺胺-6-甲氧嘧啶(DS-36)在肉鸡体内的药动学特征。结果表明:9～10周龄肉鸡单剂量(200mg/kg)口服DS-36混悬液后,血药浓度变化符合一级吸收一室开放模型,经非线性最小二乘拟合得如下动力学参数:t1/2Ka=1.50±0.92(hr)t1/2K=9.05±1.50(hr)t_(max)=4.39±1.40(hr)C_(max)=20.67±0.97(mg％)AUC=381.80±20.50(mg％.hr)据此求出多剂量给药参数,推荐的治疗方案为:负荷剂量D_0~*=236mg/kg,维持剂量D_0=200mg/kg给药间隔为24小时。此外,还对两种定量方法进行了比较。     

阿米卡星脂质体在家兔体内的药动学研究

为研究阿米卡星脂质体在家兔体内的代谢动力学,给家兔一次静注阿米卡星脂质体(12.5 mg/kg),在 24 h内不同时间点取血样测定血药浓度.结果表明:药-时曲线符合一室开放模型,其主要药代动力学参数分别为:生物半衰期(t1/2β)7.39 h,表观分布容积(V)38.43 mL,药时曲线下面积(AUC)7 487.34 h·μg/mL,清除率(CLB)3.80mL/h.     

鸡蛋中粘杆菌素残留含量消除药代动力学研究简

鸡蛋中粘杆菌素残留含量消除规律研究结果表明。鸡蛋中药物浓度-时间的药动学主要参数为：鸡蛋中药物的达峰浓度（Cmax）为（242．5641±158．7074）μg／kg,达峰时间（Tmax为（10．20668±0．93777）d,零阶矩曲线下面积（AUC）（1668．298±686．8698）μg／（ks·d）,吸收半衰期（K01-HL）（2．459439±2．255054）d,消除半衰期（K10-HL）（2．387610±1．889865）d,清除率（CL）（0．130340±0．029891）L／（kg·d）。