Intravenous administration of paclitaxel in Sprague‐Dawley rats: what is a safe dose?

Few studies describe the administration of Taxol to rats; however, rats are typically used to study the toxicity of new drugs or novel formulations. A dose finding study was conducted to determine a safe dose of Taxol following intravenous administration in rats. Male Sprague-Dawley rats received a bolus of paclitaxel 5-20 mg/kg i.v. Blood was drawn before administration and at the following times after administration: 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. Plasma concentrations were determined using high performance liquid chromatography. Two rats received paclitaxel 20 mg/kg and died immediately. Nine rats received paclitaxel 10 mg/kg; seven of these rats died within 12 h and two rats were killed due to moribund conditions. Ten rats received paclitaxel 5 mg/kg with no morbidity. The following pharmacokinetics for paclitaxel in the plasma were estimated: C0, 8977 ng/ml; AUC(0 --> infinity), 7477 ng*h/ml; CL(s), 668 ml/h*kg; V(ss), 1559 ml/kg; V(z) 2557 ml/kg and t(1/2), 2.6 h. It is concluded that further pharmacokinetic studies that are rationally designed to include appropriate measures of preclinical toxicity associated with paclitaxel are needed to identify formally the safest dose in rats following intravenous administration; however, these data indicate that male Sprague-Dawley rats can safely receive Taxol in a 5 mg/kg i.v. bolus.     

Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion

Objectives Paclitaxel is a potent anti‐cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor‐free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti‐tumour efficacy of the PSD compared with Taxol. Methods SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti‐tumor activity of PSD was assessed in an in vivo anti‐tumor nude mice model inoculated with human SKOV‐3 cancer cells. Key findings The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84‐fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti‐tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose. Conclusions These results suggest that the PSD, a CrEL‐free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.     

Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with Pluronic P123

AIM: To investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of a novel polymeric micellar formulation of paclitaxel (PTX) with Pluronic P123. METHODS: The polymeric micelles of paclitaxel with Pluronic P123 were prepared by a solid dispersion method. The characteristics of micelles including particle size distribution, morphology and in vitro release of PTX from micelles were carried out. PTX-loaded micellar solutions were administered through the tail vein to healthy Sprague-Dawley rats and Kunming strain mice to assess the pharmacokinetics and tissue distribution of PTX, respectively. Taxol, the commercially available intravenous formulation of PTX, was also administered as control. RESULTS: By using a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 25 nm with narrow size distribution and a spherical shape. PTX was continuously released from Pluronic P123 micelles in release medium containing 1 mol/L sodium salicylate for 24 h at 37 centigrade degree. In the pharmacokinetic assessment, t(1/2beta) and AUC of micelle formulation were 2.3 and 2.9-fold higher than that of Taxol injection. And the PTX-loaded micelles increased the uptake of PTX in the plasma, ovary and uterus, lung, and kidney, but decreased uptake in the liver and brain in the biodistribution study. CONCLUSION: Polymeric micelles using Pluronic P123 can effectively solubilize PTX, prolong blood circulation time and modify the biodistribution of PTX.     

Stabilized micelles as delivery vehicles for paclitaxel

Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high encapsulation efficiency of approximately 70%. Gastrointestinal transit of the developed micelles was evaluated by oral administration of rhodamine-labeled micelles in rats. Our results showed prolonged gastrointestinal residence of the marker encapsulated into micelles, compared to a solution containing free marker. Further, the oral administration of micelles in mice showed high area under curve of micellar paclitaxel (similar to the area of i.v. Taxol(?)), longer mean residence time (9-times longer than i.v. Taxol(?)) and high distribution volume (2-fold higher than i.v. Taxol(?)) indicating an efficient oral absorption of paclitaxel delivered by micelles. Intravenous administration of micelles also showed a significant improvement of pharmacokinetic parameters of micellar paclitaxel vs. Taxol(?), in particular higher area under curve (1.2-fold), 5-times longer mean residence time and lower clearance, indicating longer systemic circulation of the micelles.     

Pharmacokinetics and biodistribution of paclitaxel loaded in pegylated solid lipid nanoparticles after intravenous administration

In an effort to develop an alternative formulation of paclitaxel (PTX) suitable for intravenous administration, PTX-loaded sterically stabilized solid lipid nanoparticles (SLNs) were prepared and their pharmacokinetics and biodistribution were investigated. The pegylated SLNs were comprised of trimyristin (TM) as a solid lipid core and egg phosphatidylcholine and pegylated phospholipid as stabilizers. The prepared pegylated TM-SLNs containing PTX exhibited monodispersed size distribution with 217.4 ± 32.8 nm of mean diameter and 99% of distribution was smaller than 556.2 ± 89.9 nm. After PTX in the pegylated TM-SLNs or commercial product, Taxol?, was intravenously administered into femoral vein of rats, concentrations of PTX in plasma and organs such as liver, spleen, kidney, heart and lung were analyzed by HPLC following liquid extraction. Plasma profile of PTX for pegylated TM-SLNs was similar to that for Taxol?, with no statistically significant difference at each time point, although mean plasma levels of PTX at each point tended to be slightly lower in pegylated TM-SLNs than in Taxol?. PTX in the pegylated TM-SLNs was taken up mainly into reticuloendothelial system showing 8-fold and 3-fold higher levels in liver and spleen, respectively, 8 h after administration compared to PTX in Taxol?. Meanwhile, PTX levels in kidney, heart and lung were not different between two formulations. There were no statistically significant differences in pharmacokinetic parameters. Taken together the results, the pegylated TM-SLNs provided similar circulation compared with commercial formulation, Taxol?.     

Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability

A new, supersaturable self-emulsifying drug delivery system (S-SEDDS) of paclitaxel was developed employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S-SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC the SEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study was conducted in male Sprague-Dawley rats to assess exposure after an oral paclitaxel dose of 10 mg/kg in the SEDDS formulations with (S-SEDDS) and without HPMC. The paclitaxel S-SEDDS formulation shows approximately 10-fold higher maximum concentration (C(max)) and five-fold higher oral bioavailability (F approximately 9.5%) compared with that of the orally dosed Taxol formulation (F approximately 2.0%) and the SEDDS formulation without HPMC (F approximately 1%). Coadministration of cyclosporin A (CsA), an inhibitor of P-glycoprotein and CYP 3A4 enzyme, at a dose of 5 mg/kg with the S-SEDDS formulation further increased the oral bioavailability (F approximately 22.6%). This assessment demonstrates that the systemic exposure of paclitaxel following oral administration can be substantially improved via the S-SEDDS approach.     

In vivo pharmacokinetic and tissue distribution studies in mice of alternative formulations for local and systemic delivery of Paclitaxel: gel, film, prodrug, liposomes and micelles

The aim of this study was to increase the understanding on the pharmacokinetic and tissue distribution of paclitaxel as influenced by formulation approach. For this purpose, various formulations investigated in Swiss mice included liposomes, poloxamer 407 gel and chitosan film for subcutaneous route; and water-soluble methacrylate prodrug, liposomes and poloxamer micelles for systemic administration. During this study, the currently marketed formulation of Cremophor EL of paclitaxel was used as the reference. A highest plasma concentration following intravenous administration of paclitaxel was observed for rigid and 'Stealth((R))' liposomes containing the prodrug while, least was for covalently incorporated paclitaxel micelles. Further, poloxamer micelles demonstrated both the highest mean residence time of 7.34 h and volume of distribution (VSS=4.82 and VZ=5.87 L/kg) for paclitaxel. This was followed by prodrug loaded 'Stealth' liposomes, which showed a mean residence time of 4.96 h but were least distributed into apparent physiological volume (VSS=2.12 and VZ=3.16 L/kg). These results clearly signify the role of formulation/excipient in drug disposition and possible interactions. Importantly, due to decrease in the clearance rate of drug, the area under curve values of paclitaxel increased by 1.64- and 2.5-fold for micellar and prodrug loaded 'Stealth' liposomal formulations, respectively over reference formulation. While thermoreversible gels served to decrease plasma concentration of paclitaxel (8-fold) after subcutaneous administration, systemic levels were totally absent after implantation of films. In tissue distribution studies, maximum percent of paclitaxel was observed in liver for reference formulation, conventional liposomes and micelles whereas highest levels of prodrug and 'Stealth((R))' liposomes were in kidney and spleen, respectively. The novel formulations significantly altered tissue accumulation profiles of paclitaxel relative to the reference formulation, for example, reduction in uptake by heart from liposomes and micelles, as well as the major recognition mechanism for elimination. It is proposed that a combination therapy with liposomes and micelles of paclitaxel for systemic delivery along with implantation of chitosan film for local delivery, may serve not only to improve patient compliance by obliterating the need to administer Cremophor EL, but also increase patient survival.     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105/L101 mixed polymeric micelles

A mixed polymeric micelle formulation of paclitaxel (PTX) has been developed with the purpose of improving the solubility and prolonging the time of blood circulation of PTX in comparison to current Taxol injection. The mixed micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105, L101 and PTX. The mean size of PTX-loaded mixed micelles was 185 nm with narrow size distribution shown by a dynamic light scattering sizer and a transmission electron microscopy. The in vitro release profiles indicated that PTX release from the mixed micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic assessment in rats, in which t(1/2beta) and AUC of the mixed micelle formulation were 5.5 and 4.9-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded mixed micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood, and increased distribution of the drug in lung, spleen and kidney. These results suggested that the mixed polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for intravenous administration of PTX.     

Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

PURPOSE: The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors. METHODS: Paclitaxel SMEDDS formulation was optimized, in terms of droplet size and lack of drug precipitation following aqueous dilution, using a ternary phase diagram. Physicochemical properties of paclitaxel SMEDDS and its resulting microemulsions were evaluated. The plasma concentrations of paclitaxel were determined using a HPLC method following paclitaxel microemulsion administrations at various doses in rats. RESULTS: Following 1:10 aqueous dilution of optimal paclitaxel SMEDDS, the droplet size of resulting microemulsions was 2.0 +/- 0.4 nm, and the zeta potential was -45.5 +/- 0.5 mV. Compared to Taxol, the oral bioavailability of paclitaxel SMEDDS increased by 28.6% to 52.7% at various doses. There was a significant improvement in area under the curve (AUC) and time above therapeutic level (0.1 microM) of paclitaxel SMEDDS as compared to those of Taxol following coadministration of both formulations with 40 mg cyclosporin A (CsA)/kg. The oral absorption of paclitaxel SMEDDS slightly enhanced following coadministration of tacrolimus and etoposide, but plasma drug concentrations did not reach the therapeutic level. The nonlinear pharmacokinetic trend was not modified after paclitaxel was formulated in SMEDDS. CONCLUSIONS: The results indicate that SMEDDS is a promising novel formulation to enhance the oral bioavailability of paclitaxel, especially when coadministered with a suitable P-gp inhibitor, such as CsA.     

Pharmacokinetics of paclitaxel-containing liposomes in rats

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1±3.32 μg-h/mL; Cre-pac: 34.5±0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K_p) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K_p was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.     

P-糖蛋白抑制剂对紫杉醇大鼠体内药动学的影响

目的:比较和分析3种不同P-糖蛋白(P-glycoprotein,P-gp)抑制剂与紫杉醇注射剂(taxol)联合给予大鼠后,P-gp抑制剂对大鼠体内紫杉醇药动学行为的影响。方法:大鼠分别注射给予taxol或联合给予taxol与环孢素A、维拉帕米、槲皮素,采用HPLC测定大鼠体内紫杉醇血浆药物浓度,以3P97软件求算药动学参数。结果:环孢素A和槲皮素均能使紫杉醇大鼠体内的消除行为减缓与生物利用度提高(P<0.05或P<0.01)。维拉帕米的作用较弱(P>0.05)。结论:由于体内的紫杉醇同时受P-gp和CYP3A酶作用,因此具有P-gp和CYP3A酶双重抑制作用的环孢素A和槲皮素可显著改变紫杉醇体内的药动学行为。     

Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with pluronic P105/poly(caprolactone) copolymers

A novel polymeric micellar formulation of paclitaxel (PTX) with Pluronic/poly(caprolactone) (P105/ PCL50) has been developed with the purpose of improving in vitro release and in vivo circulating time of PTX in comparison to the current Taxol injection. This study was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of the PTX-loaded, biodegradable, polymeric, P105/PCL50 micelle system. The drug-loaded micelles were prepared by dialysis using the hydrophobic drug, PTX, and the nonionic surfactant Pluronic P105 modified with a low molecular weight PCL. The results of dynamic light scattering (DLS) experiment indicated that the PTX-loaded micelles had a mean size of approximately 150 nm with narrow size distribution (polydispersity index < 0.3). The in vitro release study showed that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic assessment in rats, in which t1/2 beta and AUC of the PTX micelle formulation were 4.0 and 2.2-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX micelle formulation not only decreased drug uptake by the liver, but also prolonged drug retention in the blood, and increased the distribution of drug in kidney, spleen, ovaries and uterus. These results suggested that the P105/ PCL50 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

Cremophor-free intravenous microemulsions for paclitaxel II. Stability, in vitro release and pharmacokinetics

Two cremophor-free microemulsion systems LBMW (lecithin:butanol:myvacet:water) and CMW (capmul:myvacet:water), for intravenous (IV) administration of paclitaxel (PAC) were previously developed and characterized. Their chemical stability, in vitro release and pharmacokinetics of PAC were assessed using Taxol (cremophor:ethanol 1:1, 6 mg/ml) as a reference. The shelf-lives of PAC at 25 degrees C in Taxol, LBMW and CMW, in an accelerated stability study, were 71, 57 and 31 days, respectively. The activation energy (Ea) for PAC in Taxol, LBMW and CMW was 23, 16 and 14 kcal/mol, respectively. PAC released from LBMW and CMW using a dialysis technique was significantly slower than that from Taxol. The extents of release of PAC from LBMW and CMW were 25 and 50% of that from Taxol. In vivo pharmacokinetic studies in male Sprague-Dawley rats after IV administration revealed that PAC in LBMW and CMW remained in the systemic circulation five and two times longer and was eight and three times more widely distributed than PAC from Taxol. LBMW and CMW offer a significant clinical advantage in terms of the prolonged half-life and wide tissue distribution, indicating that PAC delivered by these systems intravenously may result in prolonged exposure of PAC to the tumor and subsequently an improved clinical efficacy.     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles

A novel polymeric micelle formulation of paclitaxel (PTX) has been prepared with the purpose of improving in vitro release as well as prolonging the blood circulation time of PTX in comparison to a current PTX formulation, Taxol injection. This work was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of PTX-loaded Pluronic P105 micellar system. The micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105 and a hydrophobic anticancer drug, PTX. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 24 nm with narrow size distribution and a spherical shape. The in vitro release profiles indicated that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which t _1/2β and AUC of the micelle formulation were 4.9 and 5.3-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood and increased distribution of drug in lung, spleen and kidney. These results suggested that the P105 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

Effect of a thiolated polymer on oral paclitaxel absorption and tumor growth in rats

The anticancer agent paclitaxel is currently commercially available only as an infusion due to its low oral bioavailability. An oral formulation would be highly beneficial for patients. Besides the low solubility, the main reason for the limited oral bioavailability of paclitaxel is that it is a substrate of the efflux pump P-glycoprotein (P-gp). Recently, it has been demonstrated that P-gp can be inhibited by thiolated polymers. In this study, an oral paclitaxel formulation based on thiolated polycarbophil was evaluated in vivo in wild-type rats and in mammary cancer-induced rats. The paclitaxel plasma level after a single administration of paclitaxel was observed for 12 h in healthy rats. Moreover, cancer-induced rats were treated weekly for 5 weeks with the novel formulation. It was demonstrated that (1) co-administration of thiolated polycarbophil significantly improved paclitaxel plasma levels, (2) a more constant pharmacokinetic profile could be achieved and (3) the tumor growth was reduced. These effects can most likely be attributed to P-gp inhibition. According to the achieved results, thiolated polymers are believed to be interesting tools for the delivery of P-gp substrates such as paclitaxel.     

Enhanced oral bioavailability of paclitaxel by D-alpha-tocopheryl polyethylene glycol 400 succinate in mice

Paclitaxel is widely used to treat several types of solid tumors. The commercially available paclitaxel formulation contains Cremophor/ethanol as solubilizers. This study evaluated the effects of D-alpha-tocopheryl polyethylene glycol 400 succinate (TPGS 400) on the oral absorption of paclitaxel in mice. Mice were given an intravenous (18mg/kg) or oral (100mg/kg) dose of paclitaxel solubilized in Cremophor/ethanol or in TPGS 400/ethanol formulations. Paclitaxel plasma concentrations and pharmacokinetic parameters were determined. The maximal plasma concentrations of paclitaxel after an oral dose were 1.77+/-0.17 and 3.39+/-0.49microg/ml for Cremophor/ethanol and TPGS 400/ethanol formulations, respectively, with a similar time at 40-47min to reach the maximal plasma concentrations. The oral bioavailability of paclitaxel in TPGS 400/ethanol (7.8%) was 3-fold higher than that in Cremophor/ethanol (2.5%). On the other hand, the plasma pharmacokinetic profiles of intravenous paclitaxel demonstrated a superimposition for the two formulations. Furthermore, TPGS 400 concentration-dependently increased the intracellular retention of Rhodamine 123 in Caco-2 cells and enhanced paclitaxel permeability in monolayer Caco-2 cultures. TPGS 400 at concentrations up to 1mM did not inhibit testosterone 6beta-hydroxylase, a cytochrome P450 isozyme 3A in liver microsomes metabolizing paclitaxel. Our results indicated that TPGS 400 enhances the oral bioavailability of paclitaxel in mice and the enhancement may result from an increase in intestinal absorption of paclitaxel.     

Effect of a thiolated polymer on oral paclitaxel absorption and tumor growth in rats

The anticancer agent paclitaxel is currently commercially available only as an infusion due to its low oral bioavailability. An oral formulation would be highly beneficial for patients. Besides the low solubility, the main reason for the limited oral bioavailability of paclitaxel is that it is a substrate of the efflux pump P-glycoprotein (P-gp). Recently, it has been demonstrated that P-gp can be inhibited by thiolated polymers. In this study, an oral paclitaxel formulation based on thiolated polycarbophil was evaluated in vivo in wild-type rats and in mammary cancer-induced rats. The paclitaxel plasma level after a single administration of paclitaxel was observed for 12 h in healthy rats. Moreover, cancer-induced rats were treated weekly for 5 weeks with the novel formulation. It was demonstrated that (1) co-administration of thiolated polycarbophil significantly improved paclitaxel plasma levels, (2) a more constant pharmacokinetic profile could be achieved and (3) the tumor growth was reduced. These effects can most likely be attributed to P-gp inhibition. According to the achieved results, thiolated polymers are believed to be interesting tools for the delivery of P-gp substrates such as paclitaxel.     

An alternative paclitaxel microemulsion formulation: hypersensitivity evaluation and pharmacokinetic profile

Based on the clinical fact that paclitaxel injection (Taxol) frequently causes hypersensitivity reactions, we prepared an alternative paclitaxel microemulsion with small particle size (17.2 nm). The hypersensitivity evaluation and pharmacokinetic behavior in rats were conducted to assess the new microemulsion. The results showed that the new microemulsion was negative and the placebo Taxol solution was positive with regard to allergic reactions. In the pharmacokinetic study, five rats were administrated Taxol or paclitaxel microemulsion. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 14 h and paclitaxel determined by HPLC. The area under the curve (AUC) was significantly higher in the microemulsion group (34.98 microg ml(-1) h) than that in the Taxol group (21.98 microg ml(-1) h). Also, the K(10) was much smaller in the microemulsion group (0.57 h(-1)) compared with the Taxol group (1.29 h(-1)), showing the elimination rate was much slower in the former than in the latter. Compared with Taxol, the paclitaxel microemulsion caused less toxicity and had a longer circulation time in rats.     

Clinical pharmacokinetics of bretylium

Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)