Physiology of drug clearance
To understand the effects of renal impairment and hemodialysis on steady-state drug plasma concentration, it is first necessary to understand the normal physiology of renal clearance of drugs.29 Renal excretion is one route of drug . Drugs also may be eliminated entirely by hepatic excretion or other nonrenal routes, or by a combination of renal and nonrenal routes. The proportion of a drug excreted by the renal route determines the importance of renal disease in the drug’s elimination.30,31
Principles of renal clearance
Renal excretion of drugs and their metabolites is determined by three processes:
Filtration is determined primarily by glomerular filtration (measured clinically as creatinine clearance) and plasma protein binding. Only non–protein bound (free) drug in the plasma can pass through the glomerular filter. This has important implications, which are discussed later.
Some drugs are actively transported from the plasma to the urine by two independent carrier systems. One carrier system transports organic acids such as acetazolamide and glucuronide drug metabolites. The other carrier system transports organic bases such as cimetidine. In practice, the only (AED) with significant tubular secretion is acetazolamide (80% excretion via acidic secretion system).32 A small portion (probably not clinically important) of gabapentin is excreted via the basic secretion system, as evidenced by inhibition of renal clearance of gabapentin by co-administration of cimetidine.33 Otherwise, renal tubular secretion is not an important mechanism for clearance of unchanged AEDs.
Lipid-soluble (nonionized) molecules pass through biological membranes by simple diffusion, while water-soluble (ionized) molecules do not. Resorption of water in renal tubules creates a concentration gradient that facilitates back-diffusion of lipid-soluble drugs from the glomerular filtrate into the plasma. Thus, water-soluble drugs (e.g., gabapentin, levetiracetam) are excreted in the urine. Lipid-soluble drugs (e.g., carbamazepine, phenytoin) are not excreted via the urine.
The renal elimination of ionizable drugs with pKa values within the range of urinary pH (5–8) can be increased or decreased by altering urine pH. Such alterations in pH will alter the proportions of drug that are ionized (water-soluble, excreted in urine) and nonionized (lipid-soluble, resorbed into plasma). For example, alkalinization of the urine will increase the rate of elimination of phenobarbital (weak acid, pKa = 7.3) in case of phenobarbital overdose.34
In summary, the renal clearance of AEDs is determined by protein binding, glomerular filtration rate, and the drug’s water solubility. Water-soluble (ionized) drugs are excreted via the urine and lipid-soluble drugs are not. Most drug metabolites (e.g., epoxides, glucuronides) are more water-soluble than the parent drug and are excreted in the urine.
Factors determining steady-state drug plasma concentration
The mean steady-state plasma concentration of a drug during chronic oral dosing is:
Where F= fraction of drug absorbed, D= dose, t= dosing interval, Clr= renal clearance, ClH= hepatic clearance and ClO= clearance via other routes.
For drugs having no renal tubular secretion (all AEDs except acetazolamide), renal clearance can be defined as:
Where GFR= glomerular filtration rate, Cur= concentration of drug in urine, Cp= concentration of drug in plasma, and Qur= urine flow rate.
The hepatic clearance of a drug by a hepatic enzyme system is:
Where QH= hematic blood flow rate, f= free (non=protein bound) fraction of drug on plasma, Vmax= the maximum velocity of the enzyme, and KM= the Michaelis-Menten constant of the enzyme.
Combining these three equations yields:
This equation is admittedly cumbersome and complex. It need not be memorized, but it does provide a useful checklist of all the factors that may influence drug plasma concentration. Most of the factors listed in the equation can be affected by renal impairment.
Adapted from: Browne TR. Renal disorders. In: Ettinger AB and Devinsky O, eds. . Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;49-62.
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