Renal excretion of drugs. Filtration of small non-protein-bound drugs occurs through glomerular capillary pores. Lipid-soluble and un-ionized drugs are passively reabsorbed throughout the nephron. Active secretion of organic acids and bases occurs only in the proximal tubular segment.
tubular reabsorption also may have some influence on the rate of excretion for a limited number of compounds.
The ultrastructure of the glomerular capillary wall is such that it permits a high degree of fluid filtration while restricting the passage of compounds having relatively large molecular weights. This selective filtration is important in that it prevents the filtration of plasma proteins (e.g., albumin) that are important for maintaining an osmotic gradient in the vasculature and thus plasma volume.
Several factors, including molecular size, charge, and shape, influence the glomerular filtration of large molecules. The restricted passage of macromolecules can be thought of as a consequence of the presence of a glomerular capillary wall barrier with uniform pores.
Since approximately 130 mL of plasma water is filtered across the porous glomerular capillary membranes each minute (190 L/day), the kidney is admirably suited for its role in drug excretion. As the ultrafiltrate is formed, any drug that is free in the plasma water, that is, not bound to plasma proteins or the formed elements in the blood (e.g., red blood cells), will be filtered as a result of the driving force provided by cardiac pumping.
All unbound drugs will be filtered as long as their molecular size, charge, and shape are not excessively large. Compounds with an effective radius above 20 A may have their rate of glomerular filtration restricted; hindrance to passage increases progressively as the molecular radius increases, and passage approaches zero when the compound radius becomes greater than about 42A.
Charged substances (e.g., sulfated dextrans) are usually filtered at slower rates than neutral compounds (e.g., neutral dextrans), even when their molecular sizes are comparable. The greater restriction to filtration of charged molecules, particularly anions, is probably due to an electrostatic interaction between the filtered molecule and the fixed negative charges within the glomerular capillary wall. These highly anionic structural components of the wall contribute to an electrostatic barrier and are most likely in the endothelial or glomerular basement membrane regions.
Molecular configuration also may influence the rate of glomerular filtration of drugs. Differences in the three-dimensional shape of macromolecules result in a restriction of glomerular passage of globular molecules (e.g., proteins) to a greater extent than of random coil or extended molecules (e.g., dextrans). Thus, the efficient retention of proteins within the circulation is attributed to a combination of factors, including their globular structure, their large molecular size, and the magnitude of their negative charge.
Factors that affect the glomerular filtration rate (GFR) also can influence the rate of drug clearance. For instance, inflammation of the glomerular capillaries may increase GFR and hence drug filtration. Most drugs are at least partially bound to plasma proteins, and therefore their actual filtration rates are less than the theoretical GFR. Anything that alters drug-protein binding, however, will change the drug filtration rate. The usual range of half-lives seen for most drugs that are cleared solely by glomerular filtration is 1 to 4 hours. However, considerably longer half-lives will be seen if extensive protein binding occurs.
Also, since water constitutes a larger percentage of the total body weight of the newborn than of individuals in other age groups, the apparent volume of distribution of water-soluble drugs is greater in neonates. This results in a lower concentration of drug in the blood coming to the kidneys per unit of time and hence a decreased rate of drug clearance. The lower renal plasma flow in the newborn also may decrease the glomerular filtration of drugs.
An important determinant of the urinary excretion of drugs (i.e., weak electrolytes) is the extent to which substances diffuse back across the tubular membranes and reenter the circulation. In general, the movement of drugs is favored from the tubular lumen to blood, partly because of the reabsorption of water that occurs throughout most portions of the nephron, which results in an increased concentration of drug in the luminal fluid. The concentration gradient thus established will facilitate movement of the drug out of the tubular lumen, given that the lipid solubility and ionization of the drug are appropriate.
The pH of the urine (usually between 4.5 and 8) can markedly affect the rate of passive back-diffusion. The back-diffusion occurs primarily in the distal tubules and collecting ducts, where most of the urine acidification takes place. Since it is the un-ionized form of the drug that diffuses from the tubular fluid across the tubular cells into the blood, it follows that acidification increases reabsorption (or decreases elimination) of weak acids, such as salicylates, and decreases reabsorption (or promotes elimination) of weak bases, such as amphetamines. However, should the un-ionized form of the drug not have sufficient lipid solubility, urinary pH changes will have little influence on urinary drug excretion.
Effects of pH on urinary drug elimination may have important applications in medical practice, especially in cases of overdose. For example, one can enhance the elimination of a barbiturate (a weak acid) by administering bicarbonate to the patient. This procedure alka-linizes the urine and thus promotes the excretion of the now more completely ionized drug. The excretion of bases can be increased by making the urine more acidic through the use of an acidifying salt, such as ammonium chloride.
A number of drugs can serve as substrates for the two active secretory systems in the proximal tubule cells. These transport systems, which actively transfer drugs from blood to luminal fluid, are independent of each other; one secretes organic anions (Figure 4.3), and the other secretes organic cations. One drug substrate can compete for transport with a simultaneously administered or endogenous similarly charged compound; this competition will decrease the overall rate of excretion of each substance. The secretory capacity of both the organic anion and organic cation secretory systems can be saturated at high drug concentrations. Each drug will
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