The following mechanisms are involved.
Glomerular filtration. The rate at which a drug enters the glomerular filtrate depends on the concentration of free drug in plasma water and on its molecular weight. Substances that have a molecular weight in excess of 50 000 are excluded from the glomerular filtrate while those of molecular weight less than 10 000 (which includes almost all drugs)21 pass easily through the pores of the glomerular membrane.
Renal tubular excretion. Cells of the proximal renal tubule actively transfer strongly charged molecules from the plasma to the tubular fluid. There are two such systems, one for acids, e.g. penicillin, probenecid, frusemide, and another for bases, e.g. amiloride, amphetamine.
Renal tubular reabsorption. The glomerular filtrate contains drug at the same concentration as it is free in the plasma, but the fluid is concentrated progressively as it flows down the nephron so that a gradient develops, drug in the tubular fluid becoming more concentrated than in the blood perfusing the nephron. Since the tubular epithelium has the properties of a lipid membrane, the extent to which a drug diffuses back into the blood will depend on its lipid solubility, i.e. on its pKa in the case of an electrolyte, and on the pH of tubular fluid. If the fluid becomes more alkaline, an acidic drug ionises, becomes less lipid-soluble and its reabsorption diminishes, but a basic drug becomes un-ionised (and therefore more lipid-soluble) and its reabsorption increases. Manipulation of urine pH is given useful expression when sodium bicarbonate is given to alkalinise the urine to treat overdose with aspirin.
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