Age-related differences in ophthalmic drug disposition I. Effect of size on the intraocular tissue distribution of pilocarpine in albino rabbits

1981 ◽  
Vol 2 (3) ◽  
pp. 215-233 ◽  
Author(s):  
Susan C. Miller ◽  
Thomas F. Patton
Keyword(s):  
Tissue Distribution ◽  
Drug Disposition ◽  
Age Related ◽  
Ophthalmic Drug

Age-related differences in ophthalmic drug disposition III. Corneal permeability of pilocarpine in rabbits

1983 ◽  
Vol 16 (2) ◽  
pp. 203-213 ◽  
Author(s):  
Michael Francoeur ◽  
Imran Ahmed ◽  
Steve Sitek ◽  
Thomas F. Patton
Keyword(s):  
Drug Disposition ◽  
Corneal Permeability ◽  
Age Related ◽  
Ophthalmic Drug

scholarly journals O20 Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children

2019 ◽  
Vol 104 (6) ◽  
pp. e9.1-e9
Author(s):  
BD van Groen ◽  
WHJ Vaes ◽  
BK Park ◽  
EHJ Krekels ◽  
E van Duijn ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Developmental Changes ◽  
Developmentally Regulated ◽  
Age Related ◽  
Dose Linearity ◽  
Significant Difference ◽  
Therapeutic Doses ◽  
Cyp3a Enzyme

BackgroundDrug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.MethodsPreterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.ResultsOf fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.ConclusionOur data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.Disclosure(s)This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally

scholarly journals Evaluations of the Chuanqi Ophthalmic Microemulsion In Situ Gel on Dry Age-Related Macular Degeneration Treatment

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Maobo Du ◽  
Shuo Shen ◽  
Lina Liang ◽  
Kai Xu ◽  
Aiping He ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Tissue Distribution ◽  
Retinal Pigment ◽  
Vitreous Body ◽  
Age Related Macular Degeneration ◽  
Therapeutic Drug ◽  
In Situ Gel ◽  
Age Related ◽  
Dry Amd

Age-related macular degeneration (AMD) is the third largest eye disease. However, the eye has a variety of drug delivery barriers, which prevent the drug from reaching the lesions in the posterior segment of the eye, coupled with the pathogenesis of dry-AMD; these lead to the lack of effective treatment drugs for dry-AMD. Therefore, the developments of a suitable therapeutic drug and a novel ophthalmic preparation are of great significance for the treatment of dry-AMD. The purposes of this study were to construct a novel traditional Chinese medicine (Chuanqi Fang) anti-AMD microemulsion in situ gel for treating dry-AMD and investigate its characteristic, efficiency, irritation, and tissue distribution. In this study, the characteristic of the Chuanqi microemulsion in situ gel was measured by dynamic light scattering. The electroretinogram (ERG) indicators and the number of retinal pigment epithelial cells were measured to evaluate the therapeutic effect of the novel ophthalmic nanopreparations. Irritation was evaluated according to Technical Guideline Principles (ZGPT4-1). The analysis of tissue distribution was carried out with LC-MS. The research showed that the particle size of microemulsion was 38.56 ± 0.21 nm. The Chuanqi microemulsion in situ gel had certain roles in repairing retina damage of the dry-AMD animal model and showed no irritation. The tissue distribution study found that the microemulsion in situ gel could effectively deliver the drug to the posterior eye of the AMD model rat through the route of cornea-vitreous body-retina. In conclusion, this study provided a meaningful research strategy and research basis for the development of new dry-AMD therapeutic drugs.

scholarly journals Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

2021 ◽  
Vol 17 (3) ◽  
pp. e1008786
Author(s):  
Laurens F. M. Verscheijden ◽  
Carlijn H. C. Litjens ◽  
Jan B. Koenderink ◽  
Ron H. J. Mathijssen ◽  
Marcel M. Verbeek ◽  
...  
Keyword(s):  
Analgesic Effect ◽  
Drug Disposition ◽  
Opioid Analgesic ◽  
Extracellular Fluid ◽  
Older Children ◽  
Time Profiles ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Drug Concentrations ◽  
Physiologically Based

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

scholarly journals A Novel Eye Drop Candidate for Age-Related Macular Degeneration Treatment: Studies on its Pharmacokinetics and Distribution in Rats and Rabbits

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 663
Author(s):  
Eun-Jeong Choi ◽  
Go-Wun Choi ◽  
Ju Hee Kim ◽  
Hee-Woon Jang ◽  
Ju-Hee Lee ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Tissue Distribution ◽  
Compartmental Analysis ◽  
Compartment Model ◽  
Ultra Performance Liquid Chromatography ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Liquid Chromatography Tandem Mass ◽  
Active Substrate ◽  
Dry Amd

Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin® software version 8.1 (a Certara™ company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters.

Sign in / Sign up

Export Citation Format

Share Document