Three processes, one net result
How much drug ends up in the urine is decided by a tug-of-war between three steps along the nephron. Two push the drug out (glomerular filtration and tubular secretion); one pulls it back (tubular reabsorption). The net amount in urine is simply: *filtered + secreted − reabsorbed*.
Urinary excretion rate = (Filtered) + (Secreted) - (Reabsorbed) Filtered = GFR x [free drug in plasma] (passive, in glomerulus) Secreted = active transport, proximal tubule (can clear bound drug too) Reabsorbed = passive back-diffusion of lipid-soluble, un-ionized drug GFR ~ 120 mL/min in a healthy adult
Filtration: the passive sieve
At the glomerulus, blood is filtered through a sieve that lets through water and small molecules but holds back blood cells and large proteins. Crucially, only free drug crosses — a molecule bound to albumin is too big to pass. So a drug with heavy plasma protein binding is filtered slowly, because most of it is held in the blood; only the free drug fraction gets through the sieve.
Secretion: the active pump
In the proximal tubule, dedicated carrier proteins actively pump drugs from the blood into the urine — this is tubular secretion. Because it is active transport, it can move a drug even against a concentration gradient, and it can grab protein-bound drug (the transporter strips it off as free drug is consumed). Two big families exist: one for organic acids (anions) and one for organic bases (cations). Transporters like P-glycoprotein also contribute.
Reabsorption: the way back in
As filtrate flows down the tubule, water is reclaimed and the drug becomes concentrated. If the drug is lipid-soluble and un-ionized, it simply diffuses back across the tubule wall into the blood — tubular reabsorption. This is why lipid-soluble drugs are reabsorbed almost completely and need metabolism first. Reabsorption is highly sensitive to ionization, which is exactly why urinary pH can change a drug's exit speed — the topic of guide 5.