Dataset Information

Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits.

ABSTRACT: Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) (n = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 ?g · h/ml to 183.53 ?g · h/ml. Within the multidose study, mean AUCs ranged from 2.53 ?g · h/ml to 29.89 ?g · h/ml. AUCs correlated linearly within the dosage range (r = 0.97; P = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.

SUBMITTER: Petraitis V

PROVIDER: S-EPMC6125520 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits.

Petraitis Vidmantas V Petraitiene Ruta R Maung Bo Bo W BBW Khan Farehin F Alisauskaite Ieva I Olesky Melanie M Newman Joseph J Mutlib Abdul A Niu Xiaoyun X Satlin Michael M Singh Ravi S RS Derendorf Harmut H Walsh Thomas J TJ

Antimicrobial agents and chemotherapy 20180827 9

Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant <i>Enterobacteriaceae</i> We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was admi ...[more]

PMID: 29941646

Similar Datasets

Project description:The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit's eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

Project description:PPI-1011 is a synthetic plasmalogen precursor in development as a treatment for multiple plasmalogen-deficiency disorders. Previous work has demonstrated the ability of PPI-1011 to augment plasmalogens and its effects in vitro and in vivo, however, the precise uptake and distribution across tissues in vivo has not been investigated. The purpose of this study was to evaluate the pharmacokinetics, mass balance, and excretion of [14C]PPI-1011 following a single oral administration at 100 mg/kg in Sprague-Dawley rats. Further tissue distribution was examined using quantitative whole-body autoradiography after both single and repeat daily doses at 100 mg/kg/day. Non-compartmental analysis showed that following a single dose, PPI-1011 exhibited peak levels between 6 and 12 h but also a long half-life with mean t1/2 of 40 h. Mass balance showed that over 50% of the compound-associated radioactivity was absorbed by the body, while approximately 40% was excreted in the feces, 2.5% in the urine, and 10% in expired air within the first 24 h. Quantitative whole-body autoradiography following a single dose showed uptake to nearly all tissues, with the greatest initial uptake in the intestines, liver, and adipose tissue, which decreased time-dependently throughout 168 h post-dose. Following 15 consecutive daily doses, uptake was significantly higher across the entire body at 24 h compared to single dose and remained high out to 96 h where 75% of the initially-absorbed compound-associated radioactivity was still present. The adipose tissue remained particularly high, suggesting a possible reserve of either plasmalogens or alkyl diacylglycerols that the body can pull from for plasmalogen biosynthesis. Uptake to the brain was also definitively confirmed, proving PPI-1011's ability to cross the blood-brain barrier. In conclusion, our results suggest that oral administration of PPI-1011 results in high uptake across the body, and that repeated dosing over time represents a viable therapeutic strategy for treating plasmalogen deficiencies.

Dataset Information

Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits.

Publications

Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets