Cerasome Versus Liposome: A Comparative Pharmacokinetic Analysis Following Intravenous Administration into Rats
Ontology highlight
ABSTRACT:
SUBMITTER: Bahri S
PROVIDER: S-EPMC10912895 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background: TQ-B3203 is a novel topoisomerase I inhibitor currently in development for the treatment of advanced solid tumors. Great differences in pharmacokinetic characteristics were found among individuals according to the phase I clinical trial following intravenous administration of TQ-B3203 liposome injection (TLI) in Chinese patients with advanced solid tumors. Thus, it is significant to establish a population pharmacokinetic model to find the key factors and recognize their effect on pharmacokinetic parameters in order to guide individualized administration. Methods: Non-linear mixed effect models were developed using the plasma concentrations obtained from the phase I clinical trial by implementing the Phoenix NLME program. Covariates that may be related to pharmacokinetics were screened using stepwise methods. The final model was validated by goodness-of-fit plots, visual predictive check, non-parametric bootstrap and a test of normalized prediction distribution errors. Results: A three-compartment model with first-order elimination was selected as the best structural model to describe TQ-B3203 disposition adequately. Direct bilirubin (DBIL) and body mass index (BMI) were the two most influential factors on clearance, while lean body weight (LBW) was considered to affect the apparent distribution volume of the central compartment. The population estimations of clearance and central volume were typical at 3.97 L/h and 4.81 L, respectively. Model-based simulations indicated that LBW had a great impact on Cmax, BMI exerted a considerable influence on AUC0-t, and the significance of DBIL on both AUC0-t and Cmax was similarly excellent. Conclusion: The first robust population pharmacokinetic model of TQ-B3203 was successfully generated following intravenous administration of TLI in Chinese patients with advanced solid tumors. BMI, LBW and DBIL were significant covariates that affected the pharmacokinetics of TQ-B3203. This model could provide references for the dose regimen in the future study of TLI.
| S-EPMC9885713 | biostudies-literature
Project description:Objective: This phase Ia study was designed to assess the pharmacokinetic (PK) characters of free vincristine (F-VCR, refer to as non-liposomal VCR and VCR released from liposome) and total vincristine (T-VCR, the sum of both liposomal VCR and F-VCR), urinary excretion and safety of intravenous administration of vincristine sulfate liposomes injection (VSLI) in Chinese patients with malignant lymphoma and compare the results with those for conventional vincristine sulfate injection (VSI). Methods: In the phase Ia, randomized, open-label, two sequence cross-over study, patients from one group were exposed to treatment 1 including cytoxan (cyclophosphamide power injection), hydroxyrubicin (adriamycin power injection), oncovin (VSI), and prednisone tablets (standard CHOP scheme) before crossed over to treatment 2 (modified CHOP scheme in which VSI was replaced with VSLI). Patients from another group received treatments in reverse order. Results: In this phase Ia study, a total of eight subjects participated. VCR elimination from the circulation after injection of VSLI was characterized by a significantly increased maximum concentration (Cmax, 86.6 ng/mL) and plasma area under the plasma concentration-time curve from zero to infinity (AUC0-Inf, 222.1 ng/mL h), markedly decreased distribution volume (Vz, 224.1 L) and plasma clearance (CL, 8.9 L/h) compared to lower Cmax (26.6 ng/mL) and AUC0-Inf (95.1 ng/mL h), larger Vz (688.8 L) and CL (22.1 L/h) for VSI. The small proportion of F-VCR following infusion of VSLI in circulation was reflected by very low Cmax (1.8 ng/mL) and AUC0-Inf (50.5 ng/mL h). Less than 3% of the administered dose of VSLI was excreted in urine and the extent was similar to that for VSI. The elimination percentage of 40-21-14% for VSI changed to 6.2-24-39% for VSLI at intervals of 0-5, 5-13 and 13-25 h, respectively. Significant difference of toxicity between VSLI and VSI was not observed. Conclusion: VSLI exhibits higher AUC0-Inf of T-VCR, lower CL and Vz compared with VSI. VSLI was well tolerated, maybe due to the markedly decreasing AUC0-Inf of F-VCR. The majority of VCR was enveloped in liposome and VCR was released gradually from liposome following injection of VSLI. Liposomal encapsulation of VCR does not alter the route and extent of VCR excretion in urine.
| S-EPMC6123375 | biostudies-literature
Project description:Dimethylaminoethanol (DMAE) and its salts have been used to treat numerous disorders in humans and hence safety of its use is a concern. DMAE is a close structural analog of choline, an essential nutrient. Exposure to DMAE may affect choline uptake and synthesis. The current investigation characterizes: 1) the absorption, distribution, metabolism, and excretion (ADME) of DMAE in Wistar Han rats and B6C3F1 mice following a single gavage or intravenous (IV) administration of 10, 100 or 500 mg/kg [14C]DMAE, and 2) the ADME of [14C]choline (160 mg/kg) and the effect on its disposition following pre-treatment with DMAE (100 or 500 mg/kg). In both rats and mice, following gavage administration, DMAE was excreted in urine (16-69%) and as exhaled CO2 (3-22%). The tissue retention was moderate (21-44%); however, the brain concentrations were low and there was no accumulation. Serum choline levels were not elevated following administration of DMAE. The DMAE metabolites in urine were DMAE N-oxide and N,N-dimethylglycine; the carcinogen, N-N-dimethylnitrosamine, was not detected. The pattern of disposition of [14C]choline following gavage administration was similar to that of [14C]DMAE. Prior treatment with DMAE had minimal effects on choline disposition. The pattern of disposition of [14C]DMAE and [14C]choline following IV administration was similar to gavage administration. There were minimal dose-, sex- or species-related effects following gavage or IV administration of [14C]DMAE or [14C]choline. Data from the current study did not support previous reports that: 1) DMAE alters choline uptake and distribution, or 2) that DMAE is converted into choline in vivo.
| S-EPMC7252906 | biostudies-literature
Project description:Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.
| S-EPMC6466473 | biostudies-literature
Project description:We introduce a method for tracking the rate and extent of delivery of liposome contents in vivo based on encapsulation of 4-methylumbelliferyl phosphate (MU-P), a profluorophore of 4-methylumbelliferone (MU). MU-P is rapidly dephosphorylated by endogenous phosphatases in vivo to form MU after leakage from the liposome. The change in fluorescence spectra when MU-P is converted to MU allows for quantification of entrapped (MU-P) and released (MU) liposome contents by fluorescence or by a sensitive high performance liquid chromatography assay. We define the "cellular availability" of an agent encapsulated in a liposome as the ratio of the amount of released agent in the tissue to the total amount of agent in the tissue; this parameter quantifies the fraction of drug available for therapy. The advantage of this method over existing technologies is the ability to decouple the signals of entrapped and released liposome contents. We validate this method by tracking the circulation and tissue distribution of MU-P loaded liposomes after intravenous administration. We use this assay to compare the cellular availability of liposomes composed of engineered phosphocholine lipids with covalently attached cholesterol, sterol-modified lipids (SML), to liposomes composed of conventional phospholipids and cholesterol. The SML liposomes have similar pharmacokinetic and biodistribution patterns as conventional phospholipid-cholesterol liposomes but a slower rate of contents delivery into the tissue. Thus, MU-P enables the tracking of the rate and extent of liposome contents release in tissues and should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals.
| S-EPMC4040254 | biostudies-literature
Project description:Vonoprazan is characterized as having a long-lasting antisecretory effect on gastric acid. In this study we developed a physiologically based pharmacokinetic (PBPK)-pharmacodynamic (PD) model linking to stomach to simultaneously predict vonoprazan pharmacokinetics and its antisecretory effects following administration to rats, dogs, and humans based on in vitro parameters. The vonoprazan disposition in the stomach was illustrated using a limited-membrane model. In vitro metabolic and transport parameters were derived from hepatic microsomes and Caco-2 cells, respectively. We found the most predicted plasma concentrations and pharmacokinetic parameters of vonoprazan in rats, dogs and humans were within twofold errors of the observed data. Free vonoprazan concentrations (fu × C2) in the stomach were simulated and linked to the antisecretory effects of the drug (I) (increases in pH or acid output) using the fomula dI/dt = k × fu × C2 × (Imax - I) - kd × I. The vonoprazan dissociation rate constant kd (0.00246 min-1) and inhibition index KI (35 nM) for H+/K+-ATPase were obtained from literatures. The vonoprazan-H+/K+-ATPase binding rate constant k was 0.07028 min-1· μM-1 using ratio of kd to KI. The predicted antisecretory effects were consistent with the observations following intravenous administration to rats (0.7 and 1.0 mg/kg), oral administration to dogs (0.3 and 1.0 mg/kg) and oral single dose or multidose to humans (20, 30, and 40 mg). Simulations showed that vonoprazan concentrations in stomach were 1000-fold higher than those in the plasma at 24 h following administration to human. Vonoprazan pharmacokinetics and its antisecretory effects may be predicted from in vitro data using the PBPK-PD model of the stomach. These findings may highlight 24-h antisecretory effects of vonoprazan in humans following single-dose or the sustained inhibition throughout each 24-h dosing interval during multidose administration.
| S-EPMC7468366 | biostudies-literature
Project description:Trans-resveratrol (RES) is a naturally occurring stilbene found in numerous plants and foods. Due to its widespread human exposure and lack of toxicity and carcinogenicity data, RES was nominated to the National Toxicology Program for testing. To aid the toxicology studies, the dose, sex, and species differences in RES toxicokinetics was investigated in Harlan Sprague Dawley rats and B6C3F1/N mice following single intravenous (IV) (10 mg/kg) or oral gavage administration (312.5, 625, and 1250 mg/kg and 625, 1250, and 2500 mg/kg in rats and mice, respectively). Following IV and gavage administration, systemic exposure of RES based on AUC was trans-resveratrol-3-O-β-D-glucuronide (R3G)> > trans-resveratrol-3-sulfate (R3S) > RES in both species. Following gavage administration Tmax_predicted values were ≤ 263 min for both species and sexes. RES elimination half-life was longer in rats than mice, and shortest in male mice. Clearance was slower in mice with no apparent sex difference in both species. In both rats and mice, following gavage administration AUC increased proportionally to the dose. After gavage administration, enterohepatic recirculation of RES was observed in both rats and mice with secondary peaks occurring around 640 min in the concentration-time profiles. RES was rapidly metabolized to R3S and R3G in both species. Extensive first pass conjugation and metabolism resulted in low levels of the parent compound RES which was confirmed by the low estimates for bioavailability. The bioavailability of RES was low, ~12-31% and ~2-6% for rats and mice, respectively, with no apparent difference between sexes.
| S-EPMC7398575 | biostudies-literature
Project description:Bisphenol S (BPS) is a component of polyether sulfone used in a variety of industrial applications and consumer products. We investigated the plasma toxicokinetic (TK) behavior of free (unconjugated parent) and total (parent and conjugated) BPS in rats and mice following a single gavage administration (34, 110, or 340 mg/kg). In male rats, BPS was rapidly absorbed with free BPS maximum concentration (Cmax) reached at ≤2.27 h. Elimination of free BPS in male rats was dose-dependent with estimated half-lives of 5.77-11.9 h. Cmax and area under the concentration versus time curve (AUC) increased with dose although the increase in AUC was more than dose proportional. In male rats, total BPS Cmax was reached ≤2.77 h with both Cmax (≥ 10-fold) and AUC (≥ 15-fold) higher than free BPS demonstrating rapid and extensive conjugation of BPS. In male mice, the increase in Cmax and AUC of free BPS was dose-proportional; Cmax was higher and AUC was lower than in male rats. BPS was cleared more rapidly in male mice (half-life 2.86-4.21 h) compared to male rats (half-life 5.77-11.9 h). Similar to rats, total BPS Cmax (≥ 6-fold) and AUC (≥ 12-fold) were higher than corresponding free BPS. Oral bioavailability of free BPS was low to moderate (rats, ≤ 21%; mice, ≤ 19%). There were some species differences in TK parameters of free and total BPS and limited sex difference in rats and mice. In addition, there were dose-related effects of plasma TK parameters in rats.
| S-EPMC7891184 | biostudies-literature
Project description:AIM: To compare the pharmacokinetic parameters of cefuroxime lysine, a new second-generation of cephalosporin antibiotics, after intravenous (IV), intraperitoneal (IP), or intramuscular (IM) administration. METHODS: Twelve male and 12 virgin female Sprague-Dawley rats, weighing from 200 to 250 g, were divided into three groups (n=4 for each gender in each group). The rats were administered a single dose (67.5 mg/kg) of cefuroxime lysine via IV bolus or IP or IM injection. Blood samples were collected and analyzed with a validated UFLC-MS/MS method. The concentration-time data were then calculated by compartmental and non-compartmental pharmacokinetic methods using DAS software. RESULTS: After IV, IP or IM administration, the plasma cefuroxime lysine disposition was best described by a tri-compartmental, bi-compartmental or mono-compartmental open model, respectively, with first-order elimination. The plasma concentration profiles were similar through the 3 administration routes. The distribution process was rapid after IV administration [t(1/2(d)), 0.10 ± 0.11 h vs 1.36 ± 0.65 and 1.25 ± 1.01 h]. The AUMC(0-∞) is markedly larger, and mean residence time (MRT) is greatly longer after IP administration than that in IV, or IM routes (AUMC(0-∞): 55.33 ± 20.34 vs 16.84 ± 4.85 and 36.17 ± 13.24 mg·h(2)/L; MRT: 0.93 ± 0.10 h vs 0.37 ± 0.07 h and 0.65 ± 0.05 h). The C(max) after IM injection was significantly higher than that in IP injection (73.51 ± 12.46 vs 49.09 ± 7.06 mg/L). The AUC(0-∞) in male rats were significantly higher than that in female rats after IM administration (66.38 ± 16.5 vs 44.23 ± 6.37 mg·h/L). There was no significantly sex-related difference in other pharmacokinetic parameters of cefuroxime lysine between male and female rats. CONCLUSION: Cefuroxime lysine shows quick absorption after IV injection, a long retension after IP injection, and a high C(max) after IM injection. After IM administration the AUC(0-∞) in male rats was significantly larger than that in female rats.
| S-EPMC4011349 | biostudies-other
Project description: Not available
| S-EPMC6483610 | biostudies-literature