Absorption, Distribution, Metabolism, and Excretion (ADME)

ADME names the four processes a dose passes through: absorption from the site of administration, distribution into tissues and fluids, metabolism into other chemical species, and excretion of drug and metabolites out of the body. Each maps onto measurable parameters. Absorption gives bioavailability and an absorption rate constant, distribution gives volume of distribution and the bound fraction on plasma proteins, and metabolism plus excretion together give clearance, from which half-life follows.

Peptides run a different ADME course from small molecules. They are largely untouched by the cytochrome P450 enzymes that dominate small-molecule metabolism, and are instead taken apart by peptidases in gut, plasma, endothelium, liver and kidney, ending as amino acids that rejoin the body pool. Small peptides are filtered freely at the glomerulus and degraded in the proximal tubule, so renal handling matters far more than hepatic. Native glucagon-like peptide-1 is destroyed within a couple of minutes; an acylated analogue that binds albumin evades filtration and survives for days.

The framework decides which questions are worth asking about a compound. A compound cleared entirely by proteolysis and filtration has few drug interaction routes worth screening, but its exposure will change with renal function. Species differences in peptidase expression are also why rodent ADME data are a weak guide to human exposure.

Where it bites is the claim that peptides are inherently safe because they break down into amino acids. Degradation is not the same as inactivation: metabolites can retain or reverse activity, and the parent molecule still drives whatever effect is being sold. Absence of hepatic metabolism also does not mean absence of interactions, since a peptide that slows gastric emptying changes the absorption of everything swallowed with it.