Peptide Pharmacokinetics & Pharmacodynamics

Pharmacokinetics, what the body does to a drug, is comprehensively described by the ADME framework: Absorption (how the drug enters systemic circulation), Distribution (how it moves through body compartments), Metabolism (how it is chemically transformed), and Elimination (how it is removed from the body). For therapeutic peptides, each ADME component has distinct characteristics that differ fundamentally from small-molecule drugs, and understanding these differences is essential for rational prescribing, dosing schedule design, and clinical monitoring.

Absorption of parenterally administered peptides: Since most therapeutic peptides bypass the GI tract through subcutaneous or intramuscular injection, "absorption" in the pharmacokinetic sense refers to the transfer of drug from the injection site depot into systemic circulation. This process involves: (1) dissolution of the injectable formulation (if a suspension or precipitate depot is used, as with some long-acting insulin formulations); (2) diffusion from the injection site through the interstitial space; (3) uptake into capillaries (transcapillary filtration, dependent on the peptide's molecular size and charge, as smaller peptides cross capillary walls more readily) or lymphatic vessels (large peptides and proteins are preferentially absorbed via lymphatics, entering the thoracic duct and subclavian vein); (4) transport to systemic circulation. Subcutaneous administration generally provides good systemic bioavailability for peptides, although the fraction reaching the circulation varies with the peptide and the formulation (PMID 40194730)%. Factors reducing SQ bioavailability include pre-systemic catabolism of the peptide in subcutaneous tissue, local subcutaneous blood flow, and lymphatic uptake, which together make absorption of small peptides dependent on the injection site (PMID 34186147).

Distribution reflects how the drug partitions throughout the body after reaching systemic circulation. The volume of distribution (Vd) describes the apparent volume in which the drug distributes, calculated as the total amount of drug in the body divided by the plasma concentration. A Vd equal to plasma volume (~4 L for a 70 kg person) indicates the drug stays predominantly in the bloodstream. A Vd much larger than the entire body volume (70L+) indicates extensive tissue distribution. Most small linear peptides have a small volume of distribution, on the order of the plasma and extracellular fluid volumes, because they distribute poorly into cells (PMID 41661442). Albumin-bound peptides such as semaglutide have a small volume of distribution, around 7 to 8 litres, consistent with distribution largely confined to the vascular space (PMID 30788808).

Metabolism of peptides primarily involves proteolytic degradation by endopeptidases and exopeptidases in the plasma, liver, kidneys, and tissues. Unlike small-molecule drugs that are primarily metabolized by cytochrome P450 enzymes in the liver (hepatic first-pass metabolism), peptides are metabolized by ubiquitous proteases, making them susceptible to degradation at virtually any site in the body. This also means that peptide metabolism is less subject to the specific drug-drug interactions mediated by CYP enzymes, while peptide-CYP interactions exist (some peptides inhibit CYPs that they contact in the liver), they are generally less clinically significant than for small molecules (PMID 40330819). Neutral endopeptidase (NEP) and dipeptidyl peptidase-4 (DPP-4) are among the most clinically relevant enzymes degrading therapeutic peptides in vivo, NEP inactivates enkephalins, substance P, endothelin, bradykinin, natriuretic peptides and GLP-1, while DPP-4 rapidly abolishes GLP-1 activity (PMID 17704566). Elimination of peptides occurs primarily by glomerular filtration in the kidneys (for peptides below ~8 kDa renal filtration threshold), lysosomal degradation after cellular uptake via endocytosis, and fecal excretion for any orally administered fraction that is not absorbed. Hepatic biliary excretion is a minor elimination pathway for most peptides.