How the kidney excretes drugs

Only the unbound fraction of a drug in plasma is available to the glomerulus, and that fact has consequences that beginners rarely predict. The filtered load per minute is the free plasma concentration multiplied by the glomerular filtration rate. If a drug is 99% bound, the free concentration is one hundredth of the total, so the filtered load is one hundredth of what the total plasma level would suggest. Equilibrium between bound and free drug means that, as free drug is filtered, some drug dissociates from protein and replaces it, but the concentration of free drug is held at the same fractional level throughout. Raising the dose raises the total and the free concentration together, so filtration rises proportionally rather than catching up. For a drug such as warfarin, whose binding is about 99%, filtration is therefore a small door. Two practical consequences follow. First, changes in plasma protein — hypoalbuminaemia from cirrhosis, nephrosis, trauma or ageing — raise the free fraction and can produce toxicity from a dose that was previously safe. Second, if a second drug displaces the first from the same binding sites, the free level rises immediately even though the total level looks unchanged. Active secretion then becomes the main renal route by which such a drug reaches the urine.

The two proximal carriers are the kidney’s only active route for adding drug to the filtrate, and like all carrier systems they are finite. Each carrier has a limited number of sites and a maximum rate at which it can move substrate. When the concentration of a weak acid in the blood rises high enough, the anion carrier becomes saturated: adding more drug no longer increases the amount secreted per minute, and the relationship between plasma level and secretion stops being proportional. Competition is the second consequence. Because the anion carrier also handles the body’s own uric acid, a drug that shares this carrier can slow the removal of uric acid as well as of other acidic drugs, and two acidic drugs given together can each reduce the other’s secretion. In everyday terms, a steadily climbing plasma level during repeated dosing is not always caused by poor metabolism; it may be a secretion system that has reached its ceiling. The same reasoning explains why a weak acid and a weak base do not compete with each other at the proximal tubule — they use different carriers — while two weak acids often do. Clinically, saturation and competition matter most for drugs with a narrow margin between a useful and a harmful concentration, and they are a reason to look again whenever a patient’s blood level rises faster than expected.