Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained

Aggregation of composite location-aware services for mobile cellular networks

The introduction of context-aware services through service frameworks such as Open Service Access gateways in 3rd Generation networks has coincided with the increasing popularity of Business to Business (B2B) solutions such as Web Services. It is envisioned that B2B characteristics, such as service aggregation will play a part in deploying location-aware services in 3G networks. This paper examines and explores the suitability of service integration models, possible business models, the technical requirements, and suggests a framework for the aggregation and deployment of aggregated composite location-aware services. A prototype of the framework was developed and experiments involving J2EE based and Web Services/SOAP based composite services were conducted and elaborated in the paper. An analysis of the experimental results is presented at the end of the paper

Electrically driven high-Q quantum dot-micropillar cavities

We report on electrically pumped high-Q quantum dot-micropillar cavities with quality factors of up to 16.000. A special current injection scheme using a ring-shaped upper contact is presented which ensures an efficient light out-coupling through the uncapped upper surface of the micropillar. The devices feature excellent single-quantum dot cavity quantum electrodynamic effects with a Purcell enhancement of about 10 for a micropillar with a diameter of 2.5 mu m. (C) 2008 American Institute of Physics.</p