Introduction
Aprotinin is a natural proteinase inhibitor polypeptide derived from bovine lung tissue. It is a monomeric globular polypeptide which consists of a chain of 58 amino acids (C284H432N84O79S7). Aprotinin has a stable, compact tertiary structure of the 'small SS-rich" type, containing a twisted β-hairpin and a C-terminal α-helix.
Biological Activity
As a broad-spectrum serine protease inhibitor, aprotinin can inhibit many proteinases, such as chymotrypsin, kallikrein, plasmin and trypsin-among others, plasmin and plasminogen activators-which explains its antifibrinolytic properties. Through the inhibition of multiple mediators, it results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In granulocytes, it prevents the expression of pro-inflammatory adhesive glycoproteins, while in platelets, it reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa).
Function
Before Aprotinin's hemostatic applications were discovered, aprotinin had been widely used in Europe for the treatment of patients with pancreatitis and other inflammatory conditions. During studies of administration of aprotinin to reduce neutrophil activation in cardiac bypass surgery, investigators noted that the operative field was dry and that transfusion requirements for patients undergoing repeat open heart surgery were markedly reduced. Aprotinin can modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems.
Pharmacokinetics and metabolism
Aprotinin is concentrated in the kidney. From the pharmacokinetic studies, aprotinin is rapidly distributed into the extracellular compartment after intravenous administration. Plasma drug concentrations decrease biophysically, with distribution and elimination half-lives of 0.32 to 0.50 hours and 5.25 to 8.28 hours for the 2 phases, respectively. Animal studies have shown that aprotinin is primarily accumulated within the proximal tubular epithelial cells of the kidneys. After undergoing glomerular filtration, aprotinin is actively reabsorbed by the proximal tubules, stored in phagolysosomes and then gradually metabolised by lysosomal enzymes in the kidney. Approximately 25 to 40% of a single intravenous dose of 131I-labelled aprotinin was found in the urine of healthy volunteers within the first 48 hours. However, the total urinary excretion of unchanged drug is low (range 1.1 to 8.7%), but appears to increase slightly when the infused dose is increased.
References:
1. Rick Davis, Ruth Whittington. Aprotinin. Drugs, 1995, 49(6), 954-983.
2. Charles D. Bolan MD, Harvey G. Klein MD. Blood Components, Blood Products, and Pharmaceutical Agents. 2013.
