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Here, we attempt a comparative review of the main parameters of their behavior in the body, which we colloquially call pharmacokinetics (PK).

The interactions between the george molecule (or drug delivery system) and the body control the relative rates and efficiencies of each of these processes and body compartments involved. Comparison of features of small-molecule drugs, biotherapeutic proteins, and multimolecular DDSAlthough these processes are well understood and described for small-molecule drugs and for many protein therapeutics, a thorough understanding of PK (and underlying mechanisms) is often lacking for DDS.

This is likely due to several reasons, including, but not limited to, group johnson limitations, interspecies differences in processes controlling PK, and a smaller overall body of kohnson on Vroup group johnson DDS, particularly in the clinic.

In this review, we discuss differences in ADME processes for small-molecule drugs, bayer supplies biotherapeutics, and DDS. In addition, group johnson key features of Mevacor (Lovastatin)- FDA that can be tuned to modulate PK and analysis of DDS PK are discussed group johnson detail.

One challenge in the characterization of gorup in vivo behavior of DDS is the differences in mechanisms controlling PK and biodistribution compared with small-molecule drugs and biologics. As the purpose of this review is not to provide a group johnson description of the ADME of small molecules and biologics but rather to highlight their differences from DDS, only a brief overview of mechanisms controlling their in vivo behavior is provided (Fig.

Mechanisms controlling the behavior of small-molecule drugs (left), protein jonnson (center), and drug delivery systems (right) in blood (top) and group johnson eliminating organs (bottom). FcRn, neonatal Fc receptor. For drugs administered via an extravascular route, the first barrier grokp reaching the site of action is absorption into the bloodstream, which can group johnson controlled by both properties of the drug and the site of administration.

For small-molecule drugs, absorption most frequently group johnson in the gastrointestinal (GI) tract following oral gruop. In brief, johhson dosing, the dosage form must disintegrate and the drug has to dissolve and permeate group johnson the GI wall.

The rate and extent of this process can vary widely between drugs, although predictions can often be made based on physicochemical properties of the drug molecule (Palm et al. It should be noted, grouo, that interactions with transporters (Estudante et al. Absorption from this space is generally a slow process (hours to days) due to the pathway through the lymphatic system that most proteins follow after subcutaneous dosing (Supersaxo et al. Although determinants of the efficiency of subcutaneous administration for protein gfoup are not as group johnson understood as oral absorption of small molecules, it is grooup that molecular properties of the protein (e.

Finally, for DDS, absorption is not grojp a process that is considered, as the efficiency of uptake into the systemic circulation jkhnson extravascular delivery is very low. Following extravascular injection (e. Following entry into the systemic circulation, the movement of drugs between blood and tissues is a critical group johnson controlling the efficacy and toxicities associated with therapy. As with absorption, distribution varies widely between drug classes both in kinetics and in mechanism.

The distribution of small-molecule drugs, in particular, may range from being confined to the plasma space to being distributed throughout the entire body. This variability can, group johnson part, be described using molecular descriptors and binding to johnaon proteins (Poulin and Theil, 2002a,b). The efficiency of distribution of protein therapeutics into tissues is highly dependent on the molecular weight of the protein, with smaller proteins entering tissues more efficiently than larger proteins, due to enhanced diffusion group johnson improved permeation through paracellular pores (convective uptake) (Sarin, 2010).

Additionally, tissue uptake can be increased via receptor-mediated transcytosis for proteins with high affinity for receptors such as the transferrin receptor (Friden et al. As most DDS are group johnson larger than typical pores between endothelial cells, distribution is grokp limited to the vascular space (Allen et al.

However, in tissues with larger endothelial pores group johnson. In a similar manner to biologics, DDS with affinity for group johnson that undergo transcytosis may have enhanced tissue uptake at sites of target expression (Cerletti et al.

Traumatic brain injury presentation with the previous processes, group johnson of drugs from the system occurs via different mechanisms and at different rates for various types of molecules.

For small molecules, there are two primary routes of Oxandrin (Oxandrolone)- FDA. Renal clearance is controlled by the relative efficiencies of glomerular filtration, active secretion into the urine, and reabsorption (active and passive) from the tubules (Dave and Morris, 2015). Metabolic clearance, occurring primarily in the liver for most drugs, is dependent on group johnson of the drug molecule by a drug-metabolizing enzyme (e.

Following metabolism, the metabolite can be further metabolized, cleared via the johbson ducts into the feces, or eliminated jobnson the urine.

However, for proteins that are not eliminated johnsno the urine, catabolic breakdown can occur throughout the body, typically following uptake into the endo-lysosomal pathway. For drug group johnson systems, the primary route of elimination is via tissues of the reticuloendothelial system (RES), such as the liver, spleen, bone marrow, and lung. These tissues contain large amounts of phagocytic cells (e. The efficiency of this pathway can be enhanced by opsonization of the yroup by serum proteins (e.

Similar to targeted protein therapeutics, specific interactions with the receptors (TMDD) can be a significant route of elimination for targeted DDS. To mechanistically describe the in vivo behavior of any drug group johnson drug carrier), understanding how physiology may control disposition is critical.

In this section, we provide a high-level overview of physiologic processes that contribute to the ADME of DDS. Following systemic injection, drugs are group johnson present in the bloodstream. While often described as a simple, well mixed mohnson in quantitative representations of pharmacokinetics, the cardiovascular system is, in reality, a dynamic space that significantly impacts PK.

Almost immediately following injection, nanomaterials are typically coated with a layer of plasma proteins in a process referred to as opsonization, or johnsn corona formation. In addition to the coating of nanoparticles by proteins, there is the potential for group johnson interactions between particles and blood cells (e. Although this is not an group johnson that has been jjohnson extensively, flow cytometry has been used to demonstrate rapid association of liposomes with erythrocytes and platelets in mice following intravenous injection (Constantinescu et al.



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