重组人肿瘤坏死因子相关凋亡诱导配体的药代动力学和组织分布

目的研究重组人肿瘤坏死因子相关凋亡诱导配体(rhTRAIL)的药代动力学和组织分布。方法恒河猴单次静脉滴注rhTRAIL1,5和25mg.kg-1及iv5mg·kg-1后,采用酶联免疫吸附法(ELISA)测定rhTRAIL在恒河猴体内的血药浓度,并采用放射性核素示踪技术结合三氯乙酸(TCA)沉淀和分子排阻高效液相色谱法测定[125I]rhTRAIL在荷瘤裸鼠组织内的含量。结果恒河猴单次静脉滴注rhTRAIL1,5和25mg·kg-1后,各剂量组的药代参数除cmax和AUC以外,均无显著差异,表现出线性动力学性质。恒河猴每天给药1次,连续7d,药物在体内没有蓄积。恒河猴静脉滴注和iv给药对药物的体内清除过程无明显影响。[125I]标记rhTRAIL后的放化纯度大于98%。荷瘤裸鼠iv给予[125I]rhTRAIL后,在各组织广泛分布,总放射性在肿瘤组织中于给药后2h达到高峰,在其他大部分组织中于给药后10min达高峰。给药后10min及2,8和24h,肿瘤/血清的酸沉放射性比值分别为0.07±0.01,0.62±0.17,0.78±0.57和1.66±0.50;给药后24h,肿瘤组织的放射性浓度高于其他组织和血清。结论在研究剂量范围内,rhTRAIL在恒河猴体内表现为线性动力学。[125I]rhTRAIL给药后在荷瘤裸鼠中广泛分布,在肿瘤组织中分布浓度较高,并主要经肾脏排泄。     

Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat

1. The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats.

2. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1?mg/kg) and orally (5, 10 and 40?mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24?h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS.

3. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUC_inf increased in a dose-proportional manner, whereas AUC_24h and C_max exhibited a lack of dose proportionality over the dose range between 5 and 40?mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay.

4. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.

     

Pharmacokinetics, tissue distribution, excretion, and metabolism of a new cardioprotective agent 10-O-dimethylaminoethylginkgolide B in rats

The plasma pharmacokinetics, tissue distribution, excretion, and metabolism of 10-O-dimethylaminoethylginkgolide B (XQ-1H), a protective agent against cardiovascular accident for its potential anti-platelet-activating factor activity, were investigated in rats. Plasma profiles were obtained after intravenous administration of 4, 8, 16, and 32?mg/kg of XQ-1H. There was a gender difference in the pharmacokinetics of XQ-1H. The elimination half-life of XQ-1H was 209.55, 200.81, 236.95, and 269.78?min in female rats and was 139.63, 173.83, 191.28, and 228.0?min in male rats at doses of 4, 8, 16, and 32?mg/kg, respectively. At four dose levels, female rats have higher values for area under the curve (AUC) than male rats. XQ-1H had linear pharmacokinetic characteristics in rats within the dose ranges tested. The volume of distribution in rats ranged from 6.05 to 15.09?l/kg. XQ-1H showed an extensive distribution into multiple tissues and reached its maximal concentration in all tissues at 10?min post-dose. About 80% of XQ-1H was mainly converted to its hydrolyzed and demethylated metabolites in vivo, and the elimination of unchanged compound was minor (?相似文献   

Pharmacokinetics and tissue distribution of the new non-imidazole histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy) propyl]piperidine in rats

Abstract

1.?The aim of this study was to evaluate pharmacokinetics and tissue distribution of novel histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (compound DL76).

2.?Following intravenous administration of DL76 at the dose of 3?mg/kg, pharmacokinetic parameters were calculated using non-compartmental analysis. The systemic serum clearance was 10.08?L/h/kg and the estimated blood clearance was 5.64?L/h/kg. The volume of distribution at steady state was 16.1?L/kg which was greater than total body water, terminal half-life and MRT equalled 1.41?h and 1.6?h, respectively. The two-compartment pharmacokinetic model with enterohepatic circulation was also successfully fitted to the experimental data.

3.?After systemic administration, DL76 was rapidly distributed into all organs studied (liver, kidney, brain, and lung). The highest AUC of DL76 was observed in lungs followed by brain, where the exposure to the investigated compound expressed as AUC was almost 30 times higher than in serum.

4.?Bioavailability, calculated based on the area-under-the-concentration–time curve extrapolated to infinity after intravenous and intragastric administration of the dose 3?mg/kg, equalled 60.9%.     

A safety study on single intravenous dose of tetrachloro-diphenyl glycoluril [iodogen] dissolved in dimethyl sulphoxide (DMSO)

Abstract

1. Iodogen (tetrachloro-diphenyl glycoluril) dissolved in DMSO (dimethyl sulphoxide) appears indispensable in radioiodination of hypericin for a new anticancer strategy. We studied the safety of intravenously administered iodogen/DMSO in mice (n?=?132).

2. Median lethal dose (LD₅₀) of iodogen/DMSO was determined with doses of 40.0, 50.0, 55.0, 60.0, 65.0 and 70.0?mg/kg. Next, toxicity of iodogen/DMSO at 30.0?mg/kg was evaluated using saline and DMSO as controls. Changes in behaviour, body weight and serum biochemistry were evaluated. Histopathology of lungs, heart, liver and kidney was performed.

3. LD₅₀ values of iodogen/DMSO were 59.5?mg/kg (95% confidence limits (CI): 54.1–65.4?mg/kg) and 61.0?mg/kg (95%CI: 56.2–66.2?mg/kg) for female and male mice, respectively. Similar to that of control groups, no animal deaths were encountered after iodogen/DMSO administration at 30.0?mg/kg. Body weights over 24?h were not altered in all groups, but significantly higher in iodogen/DMSO and DMSO groups (p?<?0.05) 14?d post-injection. Blood urea nitrogen and alkaline phosphatase increased (p?<?0.05) in iodogen/DMSO group without clinical symptoms. No pathologies were found by gross and microscopic inspection.

4. A single dose of iodogen/DMSO up to 30.0?mg/kg, over 3000 times the dose in potential human applications, appears safe, with an LD₅₀ doubling that dose in mice.     

Blood and Plasma Lipoprotein Distribution and Gender Differences in the Plasma Pharmacokinetics of Lipid-Associated Annamycin

Abstract: The objectives of this study were to determine the lipoprotein distribution of unbound annamycin and liposomal annamycin within human and rabbit blood and plasma and to evaluate the plasma pharmacokinetics of liposomal annamycin in male and female rabbits following a single intravenous bolus of the compound. Annamycin and liposomal annamycin were incubated in human and rabbit blood and plasma for 60 min. at 37°C. Following incubation blood and plasma samples were assayed by HPLC for drug in each of the lipoprotein and lipoprotein-deficient plasma fractions. To evaluate the plasma pharmacokinetics of liposomal annamycin in male versus female rabbits, a single intravenous bolus dose (5 mg/kg) of liposomal annamycin was administered to male and female rabbits. Sequential blood samples were obtained from the animals following the dose, analyzed for drug, and the pharmacokinetics determined using multicompartmental methods. The incorporation of annamycin into liposomes composed of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol resulted in no significant differences in blood versus plasma lipoprotein drug distribution. Furthermore, no differences in the plasma distribution of liposomal annamycin were observed when the drug was either incubated in vitro for 1 hr or 1 hr following intravenous administration into New Zealand male white rabbits. The plasma clearance and volume of distribution of liposomal annamycin were decreased and a increase in plasma AUC in female as compared to male rabbits following a single intravenous bolus of liposomal annamycin was observed. These findings suggest that the lipoprotein distribution of liposomal annamycin is not different when incubated in blood or plasma and that in vitro liposomal annamycin plasma distribution is similar to in vivo. Furthermore, it appears that the pharmacokinetics of liposomal annamycin are different following administration to male versus female rabbits.     

Pharmacokinetics of lurasidone,a novel atypical anti-psychotic drug,in rats

1. This study aimed to characterise the pharmacokinetics of lurasidone, a new atypical anti-psychotic drug, in rats after intravenous and oral administration at dose range 0.5–2.5 and 2.5–10?mg/kg, respectively. Moreover, tissue distribution, liver microsomal stability and plasma protein binding were estimated.

2. After intravenous injection, systemic clearance, steady-state volumes of distribution and half-life remained unaltered as a function of dose with values in the range 22.1–27.0?mL/min/kg, 2,380–2,850?mL/kg and 229–267?min, respectively. Following oral administration, absolute oral bioavailability was not dose dependent with approximately 23%. The recoveries of lurasidone in urine and bile were 0.286% and 0.0606%, respectively.

3. Lurasidone was primarily distributed to nine tissues (brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose) and tissue-to-plasma ratios of lurasidone were ranged from 1.06 (brain) to 9.16 (adipose). Further, lurasidone was unstable in rat liver microsome and the plasma protein binding of lurasidone was concentration independent with approximately 99.6%.

4. In conclusion, lurasidone showed dose-independent pharmacokinetics at an intravenous dose of 0.5–2.5?mg/kg and an oral dose of 2.5–10?mg/kg. Lurasidone was primarily distributed to nine tissues and appeared to be primarily eliminated by its metabolism.

     

Pharmacokinetics,dose proportionality and permeability of S002-333 and its enantiomers,a potent antithrombotic agent,in rabbits

Abstract

1.?S002-333 [(2-(4′-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits.

2.?Rabbits were administered single intravenous (i.v.) (2?mg/kg) and three oral doses of 10, 20 and 40?mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers.

3.?The peak plasma concentration, after oral administration, occurred at ～10?h post-dose. The clearance (CL) and volume of distribution (V_d) after i.v. dose were found to be 3.05?±?0.09?l/h/kg and 6.73?±?1.16?l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R- and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40?mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment.

4.?In conclusion, S002-333 has low-passive permeability, low CL and large V_d. The R-enantiomer has a “slightly” greater bioavailability than the S-enantiomer.     

Pre-clinical pharmacokinetics and acute toxicological evaluation of a monastrol derivative anticancer candidate LaSOM 65 in rats

Abstract

1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats.

2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1?mg/kg) and oral (p.o., 10 and 30?mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5?mg/kg) and p.o. (50, 100 and 150?mg/kg) administration.

3. Short half-life (1.75?±?0.71?h), a clearance of 0.85?±?0.18?L/h/kg and a volume of distribution of 1.76?±?0.24?L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3?h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects.

4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate.     

Pharmacokinetics of isoforskolin after administration via different routes in guinea pigs

1.?The objective of this study was to characterize the pharmacokinetics of isoforskolin after oral, intraperitoneal and intravenous administration, as well as to compare bioavailability.

2.?Isoforskolin was administered to guinea pigs at a dose of 2?mg/kg. Plasma concentrations were determined by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (HPLC–ESI–MS/MS) method. The pharmacokinetic parameters were calculated by a noncompartmental method. A compartment model was also adopted to describe the pharmacokinetic profiles.

3.?The pharmacokinetic behavior of intravenously administered isoforskolin was characterized by rapid and extensive distribution (V_z?=?16.82?±?8.42?L/kg) followed by rapid elimination from the body (Cl?=?9.63?±?4.21?L/kg/h). After intraperitoneal administration, isoforskolin was absorbed rapidly (T_max?=?0.12?±?0.05?h). The pharmacokinetic profiles of isoforskolin were similar after intraperitoneal and intravenous administration, except for the concentrations at the initial sampling times. Isoforskolin was also absorbed rapidly following oral dosing; however, the concentration–time data were best fit to a one-compartment model, which was different from that observed after intravenous and intraperitoneal administration. Following intraperitoneal and oral administration, the absolute bioavailability of isoforskolin was 64.12% and 49.25%, respectively.

4.?Isoforskolin is a good candidate for oral administration because of its good oral bioavailability.     

Gender differences in the hepatic elimination and pharmacokinetics of lobeglitazone in rats

The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration at a dose of 1 mg/kg and oral administration at doses of 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration–time curve from time zero to infinity (AUC_inf) after intravenous administration was approximately 7.1 times higher in female rats than in male rats. In addition, the AUC_inf in the case of oral administration was at least 4.4 times higher in female rats and appeared to increase in proportion to the dose in both genders. The in vitro half‐lives were 18.8 ± 4.45 min and 60.7 ± 11.2 min, as evidenced by incubating liver microsomes obtained from male and female rats, respectively. As a result, the estimated CL_int for LB for male rat liver microsomes (0.0779 ± 0.0233 ml/min/mg protein) was much higher than that for female rat liver microsomes (0.0233 ± 0.0039 ml/min/mg protein, p < 0.05). These observations suggest that there are gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. Copyright © 2015 John Wiley & Sons, Ltd.     

Pharmacokinetics of tafamidis,a transthyretin amyloidosis drug,in rats

1.?We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3–3?mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined.

2.?After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (V_ss) and half-life (T_½) remained unaltered as a function of dose, with values in the ranges of 6.41–7.03?mL/h/kg, 270–354?mL/kg and 39.5–46.9?h, respectively. Following oral administration, absolute bioavailability was 99.7–104% and was independent of doses from 0.3 to 3?mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered.

3.?Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%.

4.?In conclusion, tafamidis showed dose-independent pharmacokinetics with intravenous and oral doses of 0.3–3?mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion.     

Genkwanin nanosuspensions: a novel and potential antitumor drug in breast carcinoma therapy

Recently, genkwanin (GKA) has been shown to display in vitro antitumor activity against some cancer cells, but its poor solubility restricted the in vivo study and further investigation of its antitumor therapeutic efficacy. In this paper, genkwanin nanosuspensions (GKA-NSps) were successfully prepared using D-alpha tocopherol acid polyethylene glycol succinate (TPGS) as a stabilizer using the precipitation-homogenization method. The obtained GKA-NSps had an average particle size of 183.1?±?4.4?nm, a PDI value of 0.16?±?0.07, a zeta potential of ?16.2?±?0.1?mV, and a drug loading content of 49.36?±?0.14%. GKA-NSps showed spherical morphology and very good stability in normal saline, phosphate buffer saline (PBS, pH 7.4), 5% glucose, artificial gastric juice, artificial intestinal juice and plasma; thus, it is suitable for both oral and intravenous administration. The resultant GKA-NSps displayed sustained drug release behavior and stronger in vitro cytotoxicity against 4T1, MCF-7, MDA-MB-453, HeLa, HepG2, BT474, and A549 cells than free GKA. The in vivo study in MCF-7 tumor-bearing nude mice indicated that GKA-NSps (60?mg/kg, i.v.) achieved similar therapeutic efficacy as PTX injection (8?mg/kg, i.v.) (62.09% vs. 61.27%), while the minimal lethal dose was more than 320?mg/kg, indicating good safety. By using nanotechnology, our study suggested that some antitumor flavonoids of low potency, such as GKA, are promising as safe but effective anticancer drugs.     

HMS-01在大鼠体内的药动学研究

目的研究HMS-01在大鼠体内的药动学,为后续研究提供支持。方法采用液相色谱-串联质谱(LCMS/MS)技术,建立灵敏、特异的测定血浆等生物样品中HMS-01浓度的分析方法,用建立的方法开展HMS-01在大鼠体内药动学研究。在SD大鼠上分别进行了1个剂量单次灌胃给药、1个剂量单次静注给药的药动学研究,以获得基本药动学参数。结果大鼠静脉注射1 mg/kg的HMS-01后,雄性与雌性大鼠血浆浓度-时间曲线下面积(AUC0-t)分别为221和409 ng·h/ml,平均清除率分别为4.53和2.41 L/h·kg,平均血浆消除半衰期分别为0.786和1.27 h,表观分布容积分别为5.13和3.82 L/kg。灌胃给予30 mg/kg的HMS-01后,在大鼠体内血浆浓度达峰时间tmax为1.17 h,达峰浓度cmax为1243 ng/ml,消除半衰期(t1/2)为2.00 h。雄、雌大鼠AUC0-t分别为2271和8529 ng·h/ml,生物利用度分别为34.3%和69.5%。结论HMS-01在大鼠体内的药动学过程存在显著的性别差异,口服吸收较好,雌性大鼠的生物利用度远高于雄性。     

Pharmacokinetics,biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration

Context: Isoliquiritigenin (ISL) has been shown to exhibit a variety of biological activities. However, there is little research on the pharmacokinetic behavior and tissues distribution of ISL.

Objective: Pharmacokinetics, biodistribution and bioavailability of ISL after intravenous and oral administration were determined by systematic investigation in Sprague–Dawley rats.

Materials and methods: ISL was dissolved in medicinal ethanol-Tween 80–0.9% sodium chloride saline in a volume ratio of 10:15:75. The ISL solution was injected in rats via a tail vein at a single dose of 10, 20 and 50?mg/kg and administered orally in rats at a single dose of 20, 50 and 100?mg/kg, respectively. Blood samples were collected at time intervals of 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8 and 12?h after intravenous injection. Tissues of interests in mice were collected immediately at each determined time point (0.5, 1, 2, 3 and 6?h) after cervical dislocation.

Results: The dose-normalized AUC values were 7.3, 7.6 and 8.7?μg?×?h/ml (calculated based on the dose of 10?mg/kg) for intravenous doses of 10, 20 and 50?mg/kg, respectively. The elimination half-lifes (t_1/2λ) were 4.9, 4.6 and 4.8?h at 10, 20 and 50?mg/kg intravenous doses, respectively. The F values were 29.86, 22.70, 33.62% for oral doses of 20, 50 and 100?mg/kg, respectively. Liver, heart and kidney were major distribution tissues of ISL in mice. The plasma protein binding of ISL in rats was 43.72%.

Conclusion: The work may useful for further study of the bioactive mechanism of ISL.     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.     

Pharmacokinetics of lurasidone, a novel atypical anti-psychotic drug, in rats

This study aimed to characterise the pharmacokinetics of lurasidone, a new atypical anti-psychotic drug, in rats after intravenous and oral administration at dose range 0.5-2.5 and 2.5-10?mg/kg, respectively. Moreover, tissue distribution, liver microsomal stability and plasma protein binding were estimated. After intravenous injection, systemic clearance, steady-state volumes of distribution and half-life remained unaltered as a function of dose with values in the range 22.1-27.0?mL/min/kg, 2,380-2,850?mL/kg and 229-267?min, respectively. Following oral administration, absolute oral bioavailability was not dose dependent with approximately 23%. The recoveries of lurasidone in urine and bile were 0.286% and 0.0606%, respectively. Lurasidone was primarily distributed to nine tissues (brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose) and tissue-to-plasma ratios of lurasidone were ranged from 1.06 (brain) to 9.16 (adipose). Further, lurasidone was unstable in rat liver microsome and the plasma protein binding of lurasidone was concentration independent with approximately 99.6%. In conclusion, lurasidone showed dose-independent pharmacokinetics at an intravenous dose of 0.5-2.5?mg/kg and an oral dose of 2.5-10?mg/kg. Lurasidone was primarily distributed to nine tissues and appeared to be primarily eliminated by its metabolism.     

Venous Irritation,Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion

Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [¹⁴C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V_ss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.     

Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution

Abstract

1.?LASSBio-1736 ((E)-1-4(trifluoromethyl) benzylidene)-5-(2-4-dichlorozoyl) carbonylhydrazine) is proposed to be an oral cysteine protease leishmanicidal inhibitor.

2.?This work aimed to investigate plasma pharmacokinetics, protein binding and tissue distribution of LASSBio-1736 in male Wistar rats.

3.?LASSBio-1736 was administered to male Wistar rats at doses of 3.2?mg/kg intravenously and 12.6?mg/kg oral and intraperitoneal. The individual plasma-concentration profiles were determined by HPLC-UV and evaluated by non-compartmental and population pharmacokinetic analysis (Monolix 2016R1, Lixoft). Tissue distribution was evaluated after iv injection of 3.2?mg/kg drug by non-compartmental approach.

4.?After intravenous administration, Vd_ss (1.79?L/kg), t _½ (23.1?h) and CL_tot (56.1?mL/h/kg) were determined, and they were statistically similar (α?=0.05) to oral and intraperitoneal pharmacokinetic parameters. The plasma profiles obtained after intravenous, oral and intraperitoneal administration of the compound were best fitted to a three-compartment and one-compartment open model with first-order absorption.

5.?The intraperitoneal and oral bioavailability were around 40 and 15%, respectively.

6.?Liver, spleen and skin tissues showed penetration of 340, 130 and 40%, respectively, with t _½ like plasma values.

7.?LASSBio-1736 protein binding was 95?±?2%.

8.?The t _½, CL_tot and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity.