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Elimination Pathways of Biologics

We talked about the absorption, the transport, the distribution. Now let’s talk about elimination pathways. For small molecules primarily, renal excretion, hepatic metabolism, and biliary secretion. And for biologics largely, proteolysis, receptor-mediated metabolism. Now renal, hepatic elimination do occur but to a much lesser extent. Non-specific proteolysis. By the protease or the peptidase, now they happen or occur intravascularly, extracellularly, and also intracellularly. For example, in the GI system, proteolysis results in low bioavailability.
And at the subcutaneous site, proteolysis results in loss of activity. And because of the non-specific proteolysis, the clearance based on pharmacokinetic model could be underestimated and that’s what I just mentioned earlier. Now let’s look at the very traditional ways of drug elimination. By renal excretion. Now renal excretion does have a cut-off molecular weight at about 3,000 daltons. Now once the biologics is filtered, it could be followed by reabsorption in the proximal tubules, for example, the IL-2, IL-11, growth hormone, and insulin. GFR could be followed by intraluminal metabolism in the distal tubule, for example, the LH-RH, the Luteinising-hormone releasing hormone. Now renal excretion is generally limited for biologics, therefore dosing regimen in renal failure is less of an issue for biologics.
However, there are always exceptions, for example, the rhIL-10, the metabolic activity is so low that renal excretion actually contribute significantly to the total clearance and therefore the total clearance correlates well with GFR and that necessitates the dosing adjustment in renal failure for rhIL-10.
Hepatic metabolism involved the uptake of biologics into the hepatocytes
and this occurs via: passive diffusion for small peptides, carrier-mediated transport for intermediate peptides, and carrier-mediated endocytosis for larger molecular protein. Let’s look at the carrier mediated transport. Here you have the biologic molecules, they become engulfed in the vesicle with the carrier, the carrier protein complex is now able to be carried through membranes. And on the other side of the membrane of the hepatocyte, then the drug is released. This is carrier mediated transport that involves a carrier and therefore this is an active transport process.
This is a little bit more complex as the carrier mediated endocytosis. It requires the drug to interact with the receptor first to form a drug-receptor complex. The complex is then joined by the carrier, in this case, the clathrin, to form an even bigger complex. This is the biologics receptor and vehicle of complex. The large size complex is then engulfed in the vesicle and then is carried through the membranes. And of course, the drug is released or the biologic is released on the other side of the membranes. And the carrier and the receptors are recycled.

In general, biologics are metabolized into small peptide fragments or amino acids that are ready for renal excretion or for recycling into protein synthesis. Metabolism happens mainly via intracellular lysosomal proteolytic degradation which occurs throughout the entire body. The traditional elimination pathways of small drugs by liver and bile is less common for biologics, although they may occur. Renal excretion is notably limited, due to the inability of the kidneys to filter large molecules. Consequently, dosing regimen adjustment with biologics is less of a concern in renal failure, however with some exceptions.

Biologics are eliminated from the body by two general pathways: metabolism/catabolism and excretion. Catabolism refers to the non-specific enzymatic degradation, for example by peptidases. This accounts for poor oral bioavailability of biologics and oral formulation is currently ruled out from consideration. Metabolism occurs mainly via intracellular lysosomal proteolytic degradation which could be either specific or non-specific. Renal excretion is limited because of molecular size being not conducive for glomerular filtration. Dosing regimen adjustment with biologics is less of a concern in renal failure, however with some exceptions (e.g., rh-IL10). It should be also noted that hepatocyte uptake can happen through carrier-mediated transport or carrier-mediated endocytosis, which constitutes part of the metabolic pathways.

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Pharmacotherapy: Understanding Biotechnology Products

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