Targeted Delivery of Hormones to Tissues by Plasma Proteins

Abstract

The sections in this article are: Organ Physiology of Solute Exchange Through Capillary Walls Quantitation of Capillary Solute Transport: Kety‐Renkin‐Crone Equation Capillary Geometry, Organ Blood Flow, and Capillary Transit Times Capillary Membrane Permeability Capillary Physiology of Steroid and Thyroid Hormone Transport Plasma Protein–Binding Kinetics Dissociation‐Limited Transport Enhanced Dissociation Mechanism of Plasma Protein–Mediated Transport Transcapillary Transport of Protein–Hormone Complex Physiology‐Based Model of Cellular Bioavailable Hormone Experimental Attempts to Measure Free Cellular Hormone Molecular Physiology of Hormone‐Binding Plasma Proteins Albumin Prealbumin (Transthyretin) Thyroid Hormone–Binding Globulin Corticosteroid‐Binding Globulin Sex Hormone–Binding Globulin α 1 ‐Acid Glycoprotein (Orosomucoid) Summary

Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin

“…However, many studies have found that in the presence of plasma protein, the net exchangeable fraction of drug in the brain capillaries markedly exceeds that measured in vitro even when correction for exchange between bound and free drug (Eq. 3) is incorporated (15,32). Our results suggest that brain influx for ibuprofen, flurbiprofen, and indomethacin correlated well with the measured free drug fraction with no evidence for a significant contribution of induced or enhanced dissociation.…”

Mechanisms and Significance of the Increased Brain Uptake of Tryptophan

“…The very high affinity of the BBB amino acid transporter is the biochemical basis for competition among the neutral amino acids for transport into the brain. Whereas the Km for neutral amino acid transport into peripheral tissues is more than one order of magnitude greater than physiological plasma amino acid concentrations, the Km for transport into the brain is much lower (6). Because the brain transporter is half saturated under physiological conditions, the neutral amino acids compete with each other for transport into the brain.…”

The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro -to- In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research

“…Conversely, other investigators reported that there is some sort of facilitation mechanism(s) going on that enhances the extracellular protein-bound drug to interact with the cell surface and dissociate from the albumin binding site to deliver more unbound drug to cells. [63][64][65][66][67] If this is true, the free drug level within the intracellular space will unexpectedly increase, which should affect the exposureeresponse relationships in the cellular fraction. In this context, it has been reported that the observed rate of hepatic uptake of compounds that are known to be highly bound to albumin in blood (e.g., more than 90%), such as free fatty acids, bile acids, as well as some organic anions and other drugs, is greater than the calculated rate of uptake from unbound concentrations.…”

“…In this context, it has been reported that the observed rate of hepatic uptake of compounds that are known to be highly bound to albumin in blood (e.g., more than 90%), such as free fatty acids, bile acids, as well as some organic anions and other drugs, is greater than the calculated rate of uptake from unbound concentrations. 45,[63][64][65][66][67] In other words, experimental data show that clearance (CL) rates for such compounds are much greater than expected based on the conventional hypothesis that only unbound drug is available for cellular uptake, suggesting the existence of a so-called albumin-mediated uptake process. Despite many attempts to identify a mechanism(s) for such phenomena, it remains largely unknown; however, five potential explanations have been proposed for the enhanced uptake of drugs in cells: (1) the facilitated dissociation of albumineligand complexes at the cell surface mediated by the plasma membrane itself or by the microclimate effect near the cell surface (e.g., conformational change), (2) the presence of ionic interactions between extracellular binding proteins and the hepatocyte surface enhance the overall uptake of ligands by a marked reduction in the diffusional distance of the extracellular proteineligand complex, (3) the rate-limiting dissociation of albumineligand complexes in the extracellular fluid that ALb is strongly attracted onto artificial and biological membrane surface.…”